I recently wrote a post about the ENCODE program that was going on. I had posted an article where it showed that geneticists have recently made a startling discovery showing that the genome and the few genes in it was only a small piece in a far bigger design that was just revealed to the researchers. I was very much mistaken (and very wrong) on the amount of knowledge of the real professional geneticists who do work in the subject. The press, the journalists, and the writers are mostly in the dark on the subject of genetics like most of the general public including me.

Let me clarify that my understanding of genetics is still at a very rudimentary level that is from 1 class in college with biochemistry and another class on basic biology. I have never taken a class on genetics, although I have sat in on one for 2 whole classes.

I always want to mention to the reader that this website is not a place for me to spew out the vast encyclopedia of height increase knowledge and information I have learned in the last 5 years. This website is a project, an on going , always evolving piece of electronic knowledge database that will be corrected when a mistake is made. I have already had to issue public apologies to organizations because I made a wrong judgement of intent.

I am learning as time goes on and I am continuously adding more and more information to my brain and this site. If you have read the most recent articles you would have noted that most of them were posts to help also myself understand the mechanics of human growth better. You can actually watch the changes being made.

This article copied and posted below was taken from the website Ars Technica HERE and written by John Timmer

Most of what you read was wrong: how press releases rewrote scientific history

Repeating myths may make good stories, but it breeds confusion. See the ENCODE news.

This week, the ENCODE project released the results of its latest attempt to catalog all the activities associated with the human genome. Although we’ve had the sequence of bases that comprise the genome for over a decade, there were still many questions about what a lot of those bases do when inside a cell. ENCODE is a large consortium of labs dedicated to helping sort that out by identifying everything they can about the genome: what proteins stick to it and where, which pieces interact, what bases pick up chemical modifications, and so on. What the studies can’t generally do, however, is figure out the biological consequences of these activities, which will require additional work.Yet the third sentence of the lead ENCODE paper contains an eye-catching figure that ended up being reported widely: “These data enabled us to assign biochemical functions for 80 percent of the genome.” Unfortunately, the significance of that statement hinged on a much less widely reported item: the definition of “biochemical function” used by the authors.

This was more than a matter of semantics. Many press reports that resulted painted an entirely fictitious history of biology’s past, along with a misleading picture of its present. As a result, the public that relied on those press reports now has a completely mistaken view of our current state of knowledge (this happens to be the exact opposite of what journalism is intended to accomplish). But you can’t entirely blame the press in this case. They were egged on by the journals and university press offices that promoted the work—and, in some cases, the scientists themselves.

To understand why, we’ll need a bit of biology and a bit of history before we can turn back to the latest results and the public response to them.

What we know about DNA, and when we knew it

Among other things, DNA has at least two key functions. First, it codes for the proteins that perform most of a cell’s functions. Second, it has control sequences that don’t encode anything, but determine when and where the coding sequences are active. We’ve had some indication that non-coding DNA played key regulatory roles since the 1960s, when the Lac operon was described and won its discoverers the Nobel Prize.

The Lac operon is present in bacterial genomes, which are under extreme pressure to carry as little DNA as possible. The typical bacterial genome is over 85 percent protein-coding DNA, leaving just a small fraction for regulatory purposes. But that isn’t generally true of vertebrates.

The coding portions of vertebrate genes turned out to be interrupted by noncoding regions, called introns. Some of these are huge—roughly a third the size of some of the smaller bacterial genomes. Vertebrate genomes also appeared to be littered with old and disabled viruses and mobile genetic parasites called transposons. Even some of the coding portions seemed a bit useless—near exact duplicates of genes were common, as were mutated and disabled copies. Many of these apparently useless pieces of DNA continued to carry sites for regulatory DNA binding proteins and continued to make RNA.

(To give you an idea of how mainstream all this was, I spent some time working on a mouse gene that was thought to be superfluous because it was a near-exact copy of a gene used by the immune system. But the copy was only expressed in males because a mobile genetic element’s regulatory sequences had been inserted nearby. And I knew all this as an undergrad in the late 1980s).

By the time we sequenced the human genome, we discovered that this seemingly useless stuff was the majority. Over half the genome was built from the remains of viruses and transposons. Introns accounted for another large fraction. And all of it seemed to be an evolutionary accident. One fish, the fugu, lacks a lot of this DNA, and seems to get along fine, while many salamanders have ten times the DNA per cell that humans do. And if you looked at the DNA of different mammals, the vast majority of it (about 95 percent) wasn’t shared by different species.

These findings seemed to support a model that was first proposed back in the 1970s, which picked up the (possibly unfortunate) moniker junk DNA. Genomic accidents—duplicating genes, picking up a virus—happen at a steady rate. Individually, these don’t cause an appreciable cost in terms of fitness, so species aren’t under a strong selective pressure to get rid of it, and pieces could linger in the genome for millions of years. But the typical bit of junk doesn’t do anything positive for the animals that carry it.

 

 

 

 

Regulatory, junk, and non-coding DNA are all partly overlapping categories, which helps foster confusion. (Circles not to scale.)

You could even consider the idea of junk DNA to be a scientific hypothesis. It notes that animal genomes experience several processes that produce superfluous bits of DNA, predicts that these will not cause enough harm to be selected for elimination, and proposes an outcome: genomes littered with random bits of history that have no impact on an organism’s fitness.

Junk dies a thousand deaths

For decades we’ve known a few things: some pieces of non-coding DNA were critically important, since they controlled when and where the coding pieces were used; but there was a lot of other non-coding DNA and a good hypothesis, junk DNA, to explain why it was there.

Unfortunately, things like well-established facts make for a lousy story. So instead, the press has often turned to myths, aided and abetted by the university press offices and scientists that should have been helping to make sure they produced an accurate story.

Discovery of new regulatory DNA isn’t usually surprising, given that we’ve known it’s out there for decades. There has been a steady stream of press releases that act as if finding a function for non-coding DNA is a complete surprise. And many of these are accompanied by quotes from scientists that support this false narrative.

The same thing goes for junk DNA. We’ve known for decades that some individual pieces of junk DNA do something useful. Introns can regulate gene expression. Bits of former virus or transposon have been found incorporated into genes or used to regulate their expression. So some junk DNA can be useful, in much the same way that a junk yard can be a valuable source of spare parts.

But it’s important to keep these in perspective. Even if a function is assigned to a piece of junk that’s 1,000 base pairs long, that only accounts for about 1/2,250,000 of the total junk that is estimated to reside in the human genome. Put another way, it’s important not to fall into the logical fallacy that finding a use for one piece of junk must mean that all of it is useful.

Despite that, many new findings in this area are accompanied by some variation on the declaration that junk is dead. Both press officers and scientists have presented a single useful piece of virus as definitively establishing that every virus, transposon, and dead gene in the human genome is essential for our collective health and survival.

A bad precedent, repeated

This brings us to the ENCODE project, which was set up to provide a comprehensive look at how the human genome behaves inside cells. Back in 2007, the consortium published its first results after having surveyed one percent of the human genome, and the results foreshadowed this past week’s events. The first work largely looked at what parts of the genome were made into RNA, a key carrier of genetic information. But the ENCODE press materials performed a sleight-of-hand, indicating that anything made into RNA must have a noticeable impact on the organism: “the genome contains very little unused sequences; genes are just one of many types of DNA sequences that have a functional impact.”

There was a small problem with this: we already knew it probably wasn’t true. Transposons and dead viruses both produce RNAs that have no known function, and may be harmful in some contexts. So do copies of genes that are mutated into uselessness. If that weren’t enough, just a few weeks later, researchers reported that genes that are otherwise shut down often produce short pieces of RNA that are then immediately digested.

So even as the paper was released, we already knew the ENCODE definition of “functional impact” was, at best, broad to the point of being meaningless. At worst, it was actively misleading.

But because these releases are such an important part of framing the discussion that follows in the popular press, the resulting coverage reflected ENCODE’s spin on its results. If it was functional, it couldn’t be junk. The concept of junk DNA was declared dead far and wide, all based on a set of findings that were perfectly consistent with it.

Four years later, ENCODE apparently decided to kill it again.

A new definition, the same problem

In the lead paper of a series of 30 released this week, the ENCODE team decided to redefine “functional.” Instead of RNA, its new definition was more DNA focused, and included sequences that display “a reproducible biochemical signature (for example, protein binding, or a specific chromatin structure).” In other words, if a protein sticks there or the DNA isn’t packaged too tightly to be used, then it was functional.

That definition nicely encompasses the valuable regulatory DNA, which controls nearby genes through the proteins that stick to it. But—and this is critical—it also encompasses junk DNA. Viruses and transposons have regulatory DNA to ensure they’re active; genes can pick up mutations in their coding sequence that leave their regulatory DNA intact. In short, junk DNA would be expected to include some regulatory DNA, and thus appear functional by ENCODE’s definition.

By using that definition, the ENCODE project has essentially termed junk DNA functional by fiat—for the second time. And perhaps more significantly, they did so two paragraphs after declaring that their results showed 80 percent of the genome was functional.

The response has been about as unfortunate as you might predict. The Nature press materials announcing the paper proclaim, “Far from being junk, the vast majority of our DNA participates in at least one biochemical event in at least one cell type.” The European Molecular Biology Laboratory’s release said that the work “revealed that much of what has been called ‘junk DNA’ in the human genome is actually a massive control panel with millions of switches regulating the activity of our genes.” MIT’s was entitled “Researchers identify biochemical functions for most of the human genome.”

But this can’t simply be blamed on the PR staff. Scientists from the National Human Genome Research Institute have been fostering the confusion. One of its program directors was quoted by UC Santa Cruz as suggesting we thought regulatory DNA was junk: “Far from being ‘junk’ DNA, this regulatory DNA clearly makes important contributions to human disease.” And its director, Eric Green, was quoted by Penn State as saying, “we can now say that there is very little, if any, junk DNA.”

This confusion leaked over to the popular press. Bloomberg’s coverage, for example, suggests we’ve never discovered regulatory DNA: “Scientists previously thought that only genes, small pieces of DNA that make up about 1 percent of the genome, have a function.” The New York Times defined junk as “parts of the DNA that are not actual genes containing instructions for proteins.” Beyond that sort of fundamental confusion, almost every report in the mainstream press mentioned the 80 percent functional figure, but none I saw spent time providing the key context about how functional had been defined.

The part in which we conclude

ENCODE remains a phenomenally successful effort, one that will continue to pay dividends by accelerating basic science research for decades to come. And the issue of what constitutes junk DNA is likely to remain controversial—I expect we’ll continue to find more individual pieces of it that perform useful functions, but the majority will remain evolutionary baggage that doesn’t do enough harm for us to eliminate it. Since neither issue is likely to go away, it would probably be worth our time to consider how we might prevent a mess like this from happening again.

The ENCODE team itself bears a particular responsibility here. The scientists themselves should have known what the most critical part of the story was—the definition of “functional” and all the nuance and caveats involved in that—and made sure the press officers understood it. Those press officers knew they would play a key role in shaping the resulting coverage, and should have made sure they got this right. The team has now failed to do this twice.

More generally, the differences among non-coding DNA, regulatory DNA, and junk DNA aren’t really that hard to get straight. And there’s no excuse for pretending that things we’ve known for decades are a complete surprise.

Unfortunately, this is a case where scientists themselves get these details wrong very often, and their mistakes have been magnified by the press releases and coverage that has resulted. That makes it much more likely that any future coverage of these topics will repeat the past errors.

If the confused coverage of ENCODE has done anything positive, it has provoked a public response by a number of scientists. Their criticisms may help convince their colleagues to be more circumspect in the future. And maybe a few more reporters will be aware that this is an area of genuine controversy, and it will help them identify a few of the scientists they should be talking to when covering it in the future.

It’s just a shame the public had to be badly misled in the process.

[Note: A Reader of the site recently contacted me and messaged that they would be interested in helping out with the site, the project, and the endeavor to find a solution to height increase. The help is much appreciated and I find that it makes my job a little easier. I wanted to give the biggest of thanks to this person who seems to not only check up on this site on a regular basis, but is also willing to contribute to the cause. Thank you.]

This is their written post on the possible use of statin to increase height and grow taller.  The amount of research and study that went into the writing is very admirable.

Statins has been long said to stimulate bone growth. Statins has also been used for wound healing and fractures. Statins are also used for slowing bone loss. Statins work by blocking the action of an enzyme in the liver that turns fatty foods into cholesterol.  Common statins used are lovastatin, simvastatin, pravastatin. Statins have also been used for osteoporosis.

Since statins work by lowering cholesterol , What is the role of cholesterol on the growth plates you must ask? Here it is:

Abstract

Inborn errors of cholesterol synthesis are associated with multiple systemic abnormalities, including skeletal malformations. The regulatory role of cholesterol during embryogenesis appears to be mediated by Shh, a signaling molecule in which activity depends on molecular events involving cholesterol. Based on this evidence, we hypothesized that cholesterol, by modifying the activity of Ihh (another of the Hedgehog family proteins) in thegrowth plate, regulates longitudinal bone growth. To test this hypothesis, we treated rats with AY 9944, an inhibitor of the final reaction of cholesterol synthesis. After 3 weeks, AY 9944 reduced the cumulative growth, tibial growth, and the tibial growth plate height of the rats. To determine whether cholesterol deficiency affects bone growth directly at the growth plate, we then cultured fetal rat metatarsal bones in the presence of AY 9944. After 4 days, AY 9944 suppressed metatarsal growth and growth plate chondrocyte proliferation and hypertrophy. The inhibitory effect on chondrocyte hypertrophy was confirmed by the AY 9944-mediated decreased expression of collagen X. Lastly, AY 9944 decreased the expression of Ihh in the metatarsal growth plate. We conclude that reduced cholesterol synthesis in the growth plate, possibly by altering the normal activity of Ihh, results in suppressed longitudinal bone growth and growth plate chondrogenesis.

Here is what Dr. Wittfield has to say about statin and its uses:

The statin-and-bone story began when Wang et al. (1995) reported that lovastatin (Mevacor) reduced steroid-induced bone loss in New Zealand rabbits. Further studies showed that atorvastatin (Lipitor), cerivastatin (Baycol [withdrawn from the market August 2001]), fluvastatin (Lescol), lovastatin and simvastatin (Zocor) stimulated cultured bone cells to make the osteogenic bone-morphogenic protein (BMP)-2 (Garrett et al., 2001a, 2001b; Hoffmann and Gross, 2001; Mundy et al., 1999; Sugiyama et al., 2000). Pravastatin (Pravachol), which only targets liver cells, had no such effect (Garrett et al., 2001b). Lovastatin and simvastatin stimulated bone formation in cultured mouse calvariae and orally gavaged simvastatin (5 mg/kg or 10 mg/kg body weight) nearly doubled trabecular bone volume and increased bone formation by 50% in ovary-intact and ovariectomized (OVX) rats (Garrett et al., 2001b; Gasper et al, 2000a, 2000b; Mundy et al., 1999). Lovastatin, either topically applied or seeping continuously from a polylactide scaffold implanted in the skin, was 50 to 80 times more effective in rats than when given orally or injected subcutaneously (Gutierrez et al., 2000; Whang et al., 2000).

Others have reported that topically or systemically administered cerivastatin, fluvastatin and simvastatin did not stimulate bone growth or prevent OVX-induced bone loss in mice and rats (Crawford et al., 2001; Sato et al., 2001; Yao et al., 2001).

Clinical record reviews of the many patients who have taken statins to lower their blood cholesterol level reported the statins did indeed significantly reduce fracturing in postmenopausal women (Bauer et el., 1999; Chan et al., 2000; Chung et al., 2000; Meier et al., 2000). The odds ratios for fracturing ranged between 0.29 and 0.61 for statin users relative to non-users. Chan et al. (2001) reported that giving simvastatin (20 mg/day for four weeks) to 17 hypercholesteremic non-osteoporotic patients increased serum osteocalcin level but not bone-specific alkaline phosphatase activity, both indicators of bone formation.

What Mundy and his research team found:

The research team first applied four different types of statins to bone taken from the skulls of mice and grown in a laboratory culture. Each of the statins increased bone growth in the cultures two to threefold by stimulating the production of osteoblasts, the specialized cells that create new bone.

“The statins build up a team of osteoblasts, but in addition to that, they bring these osteoblasts into maturity, so they can start growing bone,” Mundy said. This is in contrast to most current bone loss therapies, which only increase the number of osteoblasts without encouraging the differentiation and maturity of these bone-building cells.

The researchers tested statins in mice and in two groups of female rats, one group with intact ovaries and the other with the ovaries removed to mimic the effects of menopause. Mice that were directly injected showed an almost 50 percent increase in new bone formation in the skull after only five days of treatment. In the oral dose groups, the statins caused increases in new trabecular bone (the type of bone found at the ends of bones like the femur) ranging from 39 to 94 percent after approximately one month’s treatment.

“It was totally amazing to us,” Mundy said of the amount of bone growth, “especially the effects of it in culture and applied locally.”

He noted that the less dramatic increase in bone growth for the oral dosage groups was probably due to the fact that the orally-administered statins don’t make their way to the targeted bone as well as those that are directly injected. Since statins are designed to zero in on the liver, most of their effects on bone are secondary. For these statins to be really effective as agents against osteoporosis, Mundy said, they need to be the kind of statins that distribute themselves directly to bone or bone marrow.

Although the statins seem to be most effective at building new bone, the researchers could not rule out the possibility that the drugs were also inhibiting the breakdown of bone, which could make them a candidate for osteoporosis prevention as well.

A preliminary analysis that looked back at a group of elderly women taking statins to lower their cholesterol found that these women had higher bone mineral density and less fractures in their hip. However, Mundy cautioned that this retrospective analysis is not definitive, since the overall sample size was small and there were no controls on the length of treatment or the consistency of the statin doses. The real answer to how well these statins contribute to bone formation in humans will come after randomized clinical trials, he said.

Stimvastatin enhances pSMAD1/5/8 expression:

smad1/5/8 Is needed for chondrogenesis.

Abstract

Statins inhibit 3-hydroxy-3-methylglutarylcoen zyme A reductase, which catalyzes the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a rate-limiting step in cholesterol synthesis. A number of studies have demonstrated bone-promoting effects when simvastatin is applied locally with different carriers in various animal models. In the prsent study, the dose-dependent impact of simvastatin and bone morphogenetic protein-2 (BMP-2) on the cellular proliferation and differentiation of osteopre-cursor cells was evaluated. The alkaline phosphatase activity (ALP) test was performed to assess differentiation, and protein expression related to bone formation, including that of phospho-Smad1/5/8 (pSmad1/5/8), was measured using western blot analysis to evaluate the underlying mechanism(s). Cultures grown in the presence of 0.1 μM simvastatin with 60 ng/ml BMP-2 exhibited the highest value for ALP activity. The results of the western blot analysis indicated that the addition of simvastatin upregulated pSmad1/5/8 expression and the combination of 0.1 μM simvastatin and 60 ng/ml BMP-2 produced a significant increase in protein expression. Based on these findings, it was concluded that the combination of simvastatin and BMP-2 produced positive effects on the differentiation of osteoprecursor cells. The results also suggest that the combination of simvastatin and BMP-2 has synergistic effects that are achieved through the BMP pathway by enhancing the expression of Smad1/5/8 expression.

Abstract

STUDY DESIGN:

In vitro experiment to study the effect of simvastatin on rat intervertebral disc (IVD) cells.

OBJECTIVE:

Simvastation for invertabral disc cells~ and promotes chondrogenesis.

Hmmm spinal growth?

To evaluate the time-course effect of simvastatin on the gene expression of bone morphogenetic protein-2 (BMP-2), aggrecan, and collagen type II in rat IVD cells cultured in alginate bead. Role of BMP-2 on the simvastatin-induced chondrogenesis of IVD cells was also investigated.

SUMMARY OF BACKGROUND DATA:

Growth factors including BMP-2 have been found to improve anabolism of IVD cells and have shown promise for the treatment of disc degeneration. Statins is known to increase BMP-2 expression in vitro and stimulate bone formation in vivo. However, it is still unknown whether statins can also increase BMP-2 expression and in turn, stimulate matrix synthesis by IVD cells.

METHODS:

Rat IVD cells (harvested from nucleus pulpusos and inner annular fibrosus) cultured in alginate beads were exposed to different doses ofsimvastatin. DMMB, and real-time polymerase chain reaction were used to quantify proteoglycan and gene expression of BMP-2, aggrecan and collagen type II, respectively. Noggin or mevalonate was used to investigate the mechanism of the effect of simvastatin on rat IVD cells.

RESULTS:

Simvastatin significantly upregulated BMP-2 mRNA expression, followed by aggrecan and type II collagen gene expression and proteoglycan content in rat IVD cells. Moderate dose (500 ng/mL) of noggin completely hindered the expression of aggrecan and collagen type II induced by simvastatin on day 7, but not on day 14. The upregulated type II collagen expression was blocked with 3 mug/mL of noggin on day 14, whereas aggrecan levels remained unchanged. Lastly, simvastatin appeared to facilitate BMP-2, aggrecan, and type II collagen gene expression by inhibiting the production of mevalonate as evidenced that the anabolic effect was completely reversed with the addition of mevalonate.

CONCLUSION:

Simvastatin drives a mechanism for promoting chondrogenesis of IVD cells partially mediated by upregulated BMP-2 through the inhibition of mevalonate pathway.

Me: I wanted to end this post by stating that after looking through the old boards, the general conclusion by most height seekers on there was that statin does seem to cause bone growth, but not in the way most people would want it. It seems that the bone density increases so technically, there is bone growth but only inside the long bones, at least after the cartilage is gone. The long bones doesn’t seem to grow in the morphological sense of the word and does not actually enlarge in real form size in terms of longer or wider.

Just something to always remember and consider when looking into statin application. Overall, this post was brilliantly researched.

Me: This post will be a far more detailed analysis on the growth plate and the surrounding bones.

Interestingly, the writer of the source link is Dr. Brighton who I have done research on his work. Source link HERE. This entire post is a repost of material that Dr. Brighton has written up for a Chapter on Growth Plate growth for a class probably at the University of Pennsylvania.

CHAPTER 2 : NORMAL BONE FORMATION

SECTION ONE: EPIPHYSEAL BONE FORMATION

CARL T. BRIGHTON
Organization of the Growth Plate
Blood Supply of the Growth Plate
Structure and Function of the Growth Plate

Cartilage Component
Matrix Component
Fibrous and Fibrocartilaginous Components

The vast majority of the longitudinal growth of a typical mammalian long bone occurs at the ends of the bone in platelike structures termed growth plates. Both growth plates, one at the proximal end and the other at the distal end, are peripheral extensions of the primary center of ossification, a structure that arises in the midportion of the cartilaginous anlage of the bone-to-be during early fetal life. Originally the primary center of ossification grows and expands centrifugally in all directions. However, as it continues to expand, endochondral bone growth soon becomes confined to the growth plates (Fig. 2-1).

As growth continues, the growth plates grow away from each other. In each end of each long bone, at a time characteristic for each species of animal, a secondary center of ossification, termed the epiphysis, appears. It likewise grows and expands centrifugally in all directions, although much more slowly than did the primary center. As the distance between the growth plate and the epiphysis gradually decreases, the portion of the epiphysis that faces the growth plate closes and becomes sealed with condensed bone, termed the terminal bone plate or simply the bone plate.(78) Thereafter the epiphysis assumes a somewhat flattened hemispheric appearance and slowly fills out the remaining end of the long bone.

From the above it should be apparent that there is no single acceptable term for the growth plate proper. “Epiphyseal growth plate” or simply “epiphyseal plate” is incorrect, for these terms confuse the growth plate with the epiphysis. Rubin(48) introduced the term “physis” or “physeal segment” in an attempt to avoid this confusion. Physis, from the Greek word phyo meaning to grow or growth, is not sufficiently descriptive when referring to such a discrete morphologic structure as the growth plate. “Physeal segment” is more descriptive than physis alone, but it is a poor blending of the Greek and the English. Therefore, in order to avoid confusion and to be grammatically correct, the term growth plate will be used in this chapter.

ORGANIZATION OF THE GROWTH PLATE

The typical, fully developed growth plate in the mammalian long bone consists of various tissues acting together as a unit to perform a specialized function and, as such, is an organ. The specialized function, of course, is longitudinal growth. Based on tissue content alone, the growth plate may be divided anatomically into three components: a cartilaginous component, itself divided into various histologic zones; a bony component, or metaphysis; and a fibrous component surrounding the periphery of the plate comprising the groove of Ranvier and the perichondrial ring of LaCroix. How the growth plate synchronizes chondrogenesis with osteogenesis or interstitial cartilage growth with appositional bone growth at the same that it is growing in width, bearing load, and responding to local and systemic forces and factors is a fascinating phenomenon the key features of which are only beginning to be understood at the present time. This chapter will discuss the structure and function of the growth plate in light of those processes that are known.

BLOOD SUPPLY OF THE GROWTH PLATE

Each of the three components of the growth plate has its own distinct blood supply (Fig. 2-2). (13,16,56) The epiphyseal artery supplies the epiphysis, or the secondary center of ossification, which itself is not part of the growth plate. Small branches arise at right angles to the main epiphyseal artery in the epiphysis and pass through small cartilage canals in the reserve zone to terminate at the top of the cell columns in the proliferative zone.(56) Each small branch from the epiphyseal artery arborizes in rakelike fashion to supply the top portion of from four to ten cell columns. The proliferative zone, therefore, is well supplied with blood. None of the branches from the epiphyseal arteries penetrate the cartilage portion of the growth plate beyond the uppermost part of the proliferative zone; that is, no vessels pass through the proliferative zone to supply the hypertrophic zone.

The metaphysis is richly supplied with blood both from terminal branches of the nutrient artery as well as from the metaphyseal arteries arising from the ascending cervical arteries. The nutrient artery supplies the central region of the metaphysis, perhaps as much as four fifths of the metaphysis, while the metaphyseal vessels supply only the peripheral regions of the metaphysis. Terminal branches from the nutrient and metaphyseal arteries pass vertically toward the bone-cartilage junction of the growth plate and end in vascular loops or capillary tufts just below the last intact transverse septa at the base of the cartilage portion of the plate. The vessels turn back at this level, and venous branches descend to drain into several veins that eventually terminate in the large central vein of the diaphysis.(37,41) All (14) or most(3) of the vascular loops are closed, and microhemorrhages from the vascular loops probably do not occur. No vessels penetrate the bone cartilage junction beyond the last intact transverse septa; that is, no vessels pass from the metaphysis into the hypertrophic zone.

The fibrous peripheral structures of the growth plate, the groove of Ranvier and the perichondrial ring of LaCroix, are richly supplied with blood from several perichondrial arteries.

FIG. 2-1 Drawing depicting the two growth plates of a typical long bone toward the end of fetal life Each growth plate is a peripheral extension of the original primary center of ossification that arose in the middle portion of the cartilaginous anlage of the bone-to-be early in the fetal period.

FIG. 2-2 Drawing showing the blood supply of a typical fully developed growth plate. (Brighton CT Structure and function of the growth plate Clin Orthop 136:23 32, l978)

While the metaphysis and the fibrous peripheral components of the growth plate have an abundant blood supply, only the proliferative zone of the cartilage portion of the growth plate is adequately supplied with blood. There are no vessels in the hypertrophic zone of the fully developed growth plate; hence, that zone is entirely avascular. This avascularity has important implications for chondrocyte metabolism and matrix calcification.

The blood supply of the human femoral capital growth plate has been studied thoroughly by Chung16 and, in general, is similar to that described above for a typical growth plate. Epiphyseal arteries arising from the ascending cervical branches of the medial and lateral femoral circumflex arteries were the sole supply of the epiphysis in 82% of the femoral heads studied by Chung. However, in 28% of the femoral heads, the epiphysis was also supplied by one or two branches of the artery of the ligamentum teres femoris (Fig. 2-3). The metaphysis is supplied with blood from terminal branches of the nutrient artery as well as from metaphyseal arteries arising from the ascending cervical arteries. The fibrocartilaginous peripheral structure of the femoral capital growth plate is richly supplied with blood from several perichondrial arteries arising from the ascending cervical arteries.

STRUCTURE AND FUNCTION OF THE GROWTH PLATE CARTILAGE COMPONENT
The cartilage portion of the growth plate begins at the top of the reserve zone and ends with the last intact transverse septa at the bottom of the cell columns in the hypertrophic zone. It has been divided into various zones according to morphology or function (Fig. 2-4). The reserve zone begins just beneath the secondary bony epiphysis, followed by the proliferating zone and the hypertrophic zone. The hypertrophic zone is sometimes further subdivided into the zone of maturation, the zone of degeneration, and the zone of provisional calcification.

FIG. 2-3 Drawing showing the blood supply of the capital femoral growth plate. (RZ = reserve zone; PZ = proliferative zone; HZ = hypertrophic zone)

RESERVE ZONE

The reserve zone lies immediately adjacent to the secondary bony epiphysis. Various terms have been applied to this zone, including resting zone, zone of small-size cartilage cells, and germinal zone. However, these cells are not resting, are not small in comparison with the cells in the proliferative zone, and they are not germinal cells. They appear to store lipid and other materials and perhaps are held in reserve for later nutritional requirements. If that is true, the term reserve zone may be appropriate. The cells in this zone are spherical, exist singly or in pairs, are relatively few when compared with the number of cells in other zones, and are separated from each other by more extracellular matrix than are cells in any other zone. The cells in the reserve zone are approximately the same size as the cells in the proliferative zone.(12) The cytoplasm exhibits a positive staining reaction for glycogen. Electron microscopy reveals these cells to contain abundant endoplasmic reticulum, a clear indication that they are actively synthesizing protein. They contain more lipid bodies and vacuoles than do cells in other zones(12) but contain less glucose-6-phosphate dehydrogenase, lactic dehydrogenase, malic dehydrogenase, and phosphoglucoisomerase. (29) The zone also contains the lowest amount of alkaline and acid phosphatase,(30) total and inorganic phosphate, calcium, chloride, potassium, and magnesium.(58) The matrix in the reserve zone contains less lipid,(24) glycosaminoglycan, protein polysaccharide, moisture, and ash(35) than the matrix in any other zone. It exhibits less incorporation of radiosulfur (35S) than any other zone and also shows less Iysozyme activity than the other zones.(51) It contains the highest content of hydroxyproline of any zone in the plate. (24) Collagen fibrils in the matrix exhibit random distribution and orientation. Matrix vesicles are also seen in the matrix, but they are fewer than in other zones. The matrix shows a positive histochemical reaction for the presence of a neutral mucopolysaccharide or an aggregated proteoglycan.

Measurements of oxygen tension in the extracellular space in the different zones of the growth plate reveal PO2 to be low (20 5 + 2.1 mm Hg) in the reserve zone.(7) This probably indicates that the blood vessels that pass through this zone in cartilage canals to arborize at the top of the proliferative zone do not actually supply the reserve zone itself.

The chondrocytes in the reserve zone either do not proliferate or do so only sporadically. Therefore, the zone is not a germinal layer containing the so-called mother cartilage cells. As a matter of fact, the function of the zone is not clear. The high lipid body and vacuole content may mean that these materials are being stored for later nutritional requirements. and in this sense, the function of the zone is one of storage.

FIG. 2-4 Drawing depicting the various zones of the cartilaginous portion of the growth plate. (Brighton CT Structure and function of the growth plate. Clin Orthop 136:23 32, 1978)

PROLIFERATIVE ZONE

The spherical, single or paired chondrocytes in the reserve zone give way to flattened chondrocytes in the proliferative zone. They are aligned in longitudinal columns with the long axis of the cells perpendicular to the long axis of the bone. The cytoplasm stains positively for glycogen. Electron microscopy shows the chondrocytes to be packed with endoplasmic reticulum.(12,20) Point-counting analysis reveals the percent of the cytoplasmic area occupied by endoplasmic reticulum to increase from 14.9% at the top of the zone to 40.1% at the bottom of the zone. (12) Biochemical analyses reveal the zone of proliferation to contain the highest content of hexosamine, (19, 24) inorganic pyrophosphate,(30) and sodium, chloride, and potassium.(53) The proliferating zone shows the highest incorporation of 35S of any zone in the growth plate, and it also has the highest level of Iysozyme activity.(5l)

Tritiated thymidine autoradiographic studies have indicated that the chondrocytes in the proliferative zone are, with few exceptions, the only cells in the cartilage portion of the growth plate that divide.(25)The top cell of each column is the true “mother” cartilage cell for each column, and it is the beginning or the top of the proliferating zone that is the true germinal layer of the growth plate. Longitudinal growth in the growth plate is equal to the rate of production of new chondrocytes at the top of the proliferating zone multiplied by the maximum size of the chondrocytes at the bottom of the hypertrophic zone.(53) Kember (25) showed that the average number of new chondrocytes produced daily in each column in the growth plate of the proximal tibia in the rat was five. Since the average diameter of the chondrocyte at the bottom of the hypertrophic zone is about 30 um, the rate of growth from that particular growth plate is about 150 um/day. He further calculated that each division of a top cell in a cell column contributes 29 cells.(26) This means that each division of a top cell eventually contributes 0.9 mm of longitudinal growth to the rat tibia (29 x 30 um = 870 um). Complete growth of the rat tibia would require 40 to 50 top-cell divisions. These principles (but not the absolute numbers) presumably hold true for all mammalian growth plates.

The matrix of the proliferating zone contains collagen fibrils, distributed at random, and matrix vesicles, confined mostly to the longitudinal septa. The matrix shows a positive histochemical reaction for a neutral mucopolysaccharide or an aggregated proteoglycan.

Oxygen tension is higher in the proliferating zone (57 +/- 5.8 mm Hg) than in any of the other zones of the growth plate.(7) This is due to the rich vascular supply present at the top of the zone. Considering the relatively high oxygen tension coupled with the presence of glycogen in the chondrocytes, it is apparent that aerobic metabolism with glycogen storage is occurring.

Thus the function of the proliferative zone is twofold: matrix production and cellular proliferation. The combination of these two functions equals linear or longitudinal growth. It is a paradox that while this chondrogenesis or cartilage growth is solely responsible for the increase in linear growth of the long bone, the cartilage portion of the plate itself does not increase in length. This, of course, is due to the vascular invasion that occurs from the metaphysis with the resultant removal of chondrocytes at the bottom of the hypertrophic zone, events that, in the normal growth plate, exquisitely balance the rate of cartilage production.

HYPERTROPHIC ZONE

The flattened chondrocytes in the proliferative zone become spherical and greatly enlarged in the hypertrophic zone. These changes in cell morphology are quite abrupt, and one can usually determine the end of the proliferative zone and the beginning of the hypertrophic zone within an accuracy of one to two cells. By the time the average chondrocyte reaches the bottom of the hypertrophic zone, it has enlarged some five times over what its size was in the proliferative zone.(12) The cytoplasm of the chondrocytes in the top half of the hypertrophic zone stains positively for glycogen (periodic acid-Schiff [PAS] reaction coupled with diastase digestion), but near the middle of the zone the cytoplasm abruptly loses this ability. On light microscopy, the chondrocytes in the hypertrophic zone appear vacuolated. Toward the bottom of the zone, such vacuolation becomes extensive, nuclear fragmentation occurs, and the cells appear nonviable. At the very bottom of each cell column the lacunae appear empty and are devoid of any cellular content.

On electron microscopy the chondrocytes in the top half of the hypertrophic zone appear normal and contain the full complement of cytoplasmic components. (12,21) However, in the bottom half of the zone, the cytoplasm contains holes that occupy over 58% of the total cytoplasmic column. (12) Obviously, it is holes and not vacuoles that account for the “vacuolation” seen on light microscopy. Electron microscopy also shows that glycogen is abundant in the chondrocytes in the top half of the zone, diminishes rapidly in the middle of the zone, and disappears completely from the cells in the bottom portion of the zone. The last cell at the base of each cell column is clearly nonviable and shows extensive fragmentation of the cell membrane and the nuclear envelope with loss of all cytoplasmic components except a few mitochondria and scattered remnants of endoplasmic reticulum. Clearly, the ultimate fate of the hypertrophic chondrocyte is death.

Electron micrographs reveal electron-dense granules in mitochondria of growth plate chondrocytes.(35,39) These granules are not removed by microincineration(39) (and hence, are mineral) and have been shown by direct analysis to have the characteristic radiographic spectra of calcium and phosphorus.(55) They are present in highest concentration in chondrocytes in the hypertrophic zone in the normal growth plate and are absent or greatly diminished in number in the rachitic growth plate.(49) Histochemical localization of calcium at the ultrastructural level shows the mitochondria and cell membranes of chondrocytes in the top half of the hypertrophic zone to be loaded with calcium (Fig. 2-5). (8,9) Toward the middle of the zone, mitochondria rapidly lose calcium, and at the bottom of the zone, both mitochondria and cell membranes are totally devoid of calcium. All of these studies cited above provide circumstantial evidence that mitochondrial calcium may be involved in cartilage calcification.

FIG. 2-5 Electron micrographs of mitochondria from the hypertrophic zone of the growth plate stained for calcium with potassium pyroantimonate. (A) Top portion of the hypertrophic zone stained conventionally. (B) Top portion of the hypertrophic zone showing positive stain in mitochondria. (C) Middle portion of the hypertrophic zone showing beginning of depletion of calcium stain from the mitochondria. (D) Bottom of hypertrophic zone showing almost complete depletion of mitochondrial calcium. (original magnification x 82,000)

Biochemical analyses of the hypertrophic zone indicate that this region, or at least the upper three fourths of it, is active metabolically. It contains the highest content of alkaline phosphatase, acid phosphatase, glucose-6-phosphate dehydrogenase, lactic dehydrogenase, malic dehydrogenase and phosphoglucoisomerase;(29,30) total and inorganic phosphate, calcium, and magnesium;(58) moisture and ash;(35) and lipid.(24) It contains the lowest content of hydroxyproline(24) and hexosamine(19)

Oxygen tension in the hypertrophic zone is quite low (24.3 +/- 2.4 mm Hg).(7) No doubt this low oxygen tension is due to the avascularity of the zone.

FIG. 2-6 Drawing summarizing the metabolic events occurring in the various zones of the growth plate. (Brighton CT, Hunt RM: The role of mitochondria in growth plate calcification as demonstrated in a rachitic model. J Bone Joint Surg 60A:630 639, 1978)

A summary of the metabolic events occurring in the cartilage portion of the growth plate, or, more correctly, in the proliferative and hypertrophic zones, is presented in Figure 2-6. (10) In the proliferative zone, oxygen tension is high, aerobic metabolism occurs, glycogen is stored, and mitochondria form adenosine triphosphate (ATP). Mitochondria can form ATP or store calcium, but they cannot do both at the same time.(33) Thus, ATP formation and calcium accumulation are alternative processes rather than simultaneous ones. In the proliferative zone, the energy requirement for matrix production and cellular proliferation is high, and mitochondria form ATP. In the hypertrophic zone, oxygen tension is low, anaerobic metabolism occurs, and glycogen is consumed until, near the middle of the zone, it is completely depleted. In the top half of the hypertrophic zone, mitochondria switch from forming ATP to accumulating calcium.(3) Why this switch occurs at this level in the growth plate is not entirely clear. However, both the formation of ATP and calcium accumulation are active processes requiring energy.(33) Such energy comes from the respiratory chain in the mitochondria. ATP formation requires, in addition, the presence of adenosine diphosphate (ADP), while calcium accumulation does not. It may well be that in the hypertrophic zone there simply is not enough ADP to provide for significant ATP formation. In any event, mitochondria in the top half of the hypertrophic zone accumulate calcium and do not form ATP.

In the bottom half of the hypertrophic zone, as stated above, glycogen is completely depleted. In this area of low oxygen tension, there is no other source of nutrition to serve as an energy source for the mitochondria. Since retention of calcium by mitochondria (as well as uptake of calcium) is an active process requiring energy,(34) as soon as the glycogen supply of the chondrocytes is exhausted, mitochondria release calcium. This released calcium may play a role in matrix calcification (see below).

The matrix of the hypertrophic zone, unlike the other zones, shows a positive histochemical reaction for an acid mucopolysaccharide or a disaggregated proteoglycan. Electron microscopy reveals that there is a progressive decrease in length of proteoglycan aggregates and a decrease in the number of subunits of the aggregates in the matrix as one progresses from the reserve zone through the hypertrophic zone.(15) The distance between the subunits increases at the same time. It is speculated by some that the large proteoglycan aggregates with tightly packed subunits may inhibit mineralization or the spread of mineralization, whereas smaller aggregates with widely spaced subunits at the bottom of the hypertrophic zone may be less effective in preventing mineral growth.(15) Lysozyme may be involved in the disaggregation of large proteoglycan aggregates,(28,42,51) or Iysosomal enzymes, especially neutral proteases, may degrade the proteoglycan.(49) In any event, it seems apparent that proteoglycan disaggregation or degradation must occur before there can be significant mineralization.(27,23)

The initial calcification (“seeding” or “nucleation”) that occurs in the growth plate in the bottom of the hypertrophic zone (zone of provisional calcification) does so within or upon matrix vesicles that are present in the longitudinal septa of the matrix (Fig. 2-7).(1,4,5,18)Matrix vesicles are very small structures (lOOOA-1500A in diameter) that are enclosed in a trilamellar membrane and, therefore, are produced by the chondrocyte. They occur in greatest concentration in the hypertrophic zone.(4) Matrix vesicles are rich in alkaline phosphatase,(2) and this enzyme may act as a pyrophosphatase to destroy pyrophosphate, another inhibitor of calcium phosphate precipitation.(18) Matrix vesicles begin to accumulate calcium at the same level in the middle of the hypertrophic zone at which mitochondria begin to lose calcium (Fig. 2-8).(5-9) This is circumstantial evidence indicating that mitochondrial calcium is involved in the initial calcification that occurs in the growth plate. The initial calcification in the matrix vesicles may be in the form of amorphous calcium phosphate,(43) but this rapidly gives way to hydroxyapatite crystal formation. With crystal growth and confluence, the longitudinal septa become calcified. This occurs in the bottom portion of the hypertrophic zone, a region frequently called the zone of provisional calcification.

This calcification makes the intercellular matrix relatively impermeable to metabolites. Diffusion coefficients of the various zones of the growth plate have been measured, and the hypertrophic zone has the lowest diffusion coefficient in the entire growth plate.(54) This is due primarily to the high mineral content of that zone, and suggests the following sequence of events:

1. Calcification occurs.
2. Diffusion of nutrients and oxygen to the hypertrophic chondrocyte is decreased.
3. Anaerobic glycolysis with glycogen consumption occurs until all the glycogen is depleted.
4. Mitochondria release calcium.
5. Nucleation occurs in the matrix vesicles.
6. Calcification of the matrix occurs.

FIG. 2-7 Electron micrographs of matrix vesicles from the various zones of the growth plate stained for calcium with potassium pyroantimonate. (A) Proliferative zone stained conventionally. (B) Proliferative zones stained with pyroantimonate (negative stain). (C) Middle of hypertrophic zone shows clumps of calcium-antimonate complex upon or within matrix vesicles. (D) Bottom of hypertrophic zone shows crystal formation obliterating the matrix vesicle. (original magnification x 180,000).

Thus, a cycle is established that results ultimately in the death of the hypertrophic chondrocyte (Fig. 2-9).

The functions of the hypertrophic zone seem clear: to prepare the matrix for calcification and to calcify the matrix. Although these processes are complex biophysical phenomena, it is evident from the studies cited above that we are beginning to unravel the mechanisms and factors controlling matrix calcification.

BONY COMPONENT (METAPHYSIS)

The metaphysis begins just distal to the last intact transverse septum at the base of each cell column of the cartilage portion of the growth plate (Fig. 2-10). It ends at the point at which narrowing or funnelization of the bone end ceases, that is, where the wider metaphysis meets the narrower diaphysis.(48) In the first part of the metaphysis just distal to the cartilage portion of the plate, the oxygen tension is low (19.8 + 3.2 mm Hg).(7) The low oxygen tension, as well as the rouleaux formation of the red cells frequently seen just distal to the last intact transverse septa,(6) indicates that this is a region of vascular stasis. A flocculent, electron-dense material present within the lumen of vascular sprouts invading the transverse septa may likewise indicate the presence of circulatory stasis within these vessels.(50)Also, high levels of phosphoglucoisomerase, an enzyme active in anaerobic metabolism, are found in this region and are compatible with vascular stasis(29)

In the first part of the metaphysis, the first lacuna distal to the last intact transverse septum at the base of each column of cells is, by light microscopy, either empty or contains one or more red cells. Electron microscopy shows capillary sprouts or loops lined by a layer of endothelial and perivascular cells invading the base of the cartilage portion of the plate.(50) Cytoplasmic processes from these cells push into the transverse septa and, presumably through Iysosomal enzyme activity, degrade and remove the nonmineralized transverse septa. At this same level in the metaphysis, the longitudinal septa are partially or completely calcified. Osteoblasts, which are plump, oval-shaped cells with eccentric nuclei, line up along the calcified bars. Between the osteoblasts lining the calcified bars and the capillary sprouts are seen osteoprogenitor cells, cells with little cytoplasm but with a prominent ovoid to spindle-shaped nucleus(27) This region of vascularized calcified cartilage with little or no bone formation occurring on the calcified bars is termed the primary spongiosum.(36)

FIG. 2-8 Montage of electron micrographs of the hypertrophic zone shows that the calcium-antimonate staining is predominantly intracellular at the top of the zone but becomes progressively more extracellular toward the bottom of the zone. The inserts on the right are of mitochondria in chondrocytes at corresponding levels in the zone. Note the gradual loss of the calcium stain the farther down the zone the mitochondrion is located. Inserts on the left are of matrix vesicles at corresponding levels in the zone. Note the gradual accumulation of the calcium stain the farther down the zone the vesicle is located. (Brighton CT, Hunt RM: Mitochondral calcium and its role in calcification. Clin Orthop 100:406 416, 1974)

FIG. 2-9 Drawing showing events in the hypertrophic zone relating matrix calcification to decrease pO2, glycogen metabolism, and mitochondrial, calcium release (Brighton CT, Hunt RM: The role of mitochondria in growth plate calcification as demonstrated in a rachitic model. J Bone Joint Surg 60A:630 638, 1978)

FIG. 2-10 Drawing of the metaphysis showing the interlocking of the primary and secondary spongiosa. (Brighton CT: Structure and function of the growth plate. Clin Orthop 136:23-32, 1978)

A short distance (within a cell or two) further down the calcified longitudinal septa, the osteoblasts begin laying down bone (termed endochondral ossification, i.e., bone formation within or upon cartilage). The further down or into the metaphysis one progresses, the more bone is formed on the calcified cartilage bars. At the same time, the bars gradually diminish in thickness until they disappear altogether. This region, where bone is laid down on calcified cartilage bars, is termed the secondary spongiosum.(36)

Still further down in the metaphysis, the fiber bone that was formed originally is replaced with lamellar bone. This gradual replacement of the calcified longitudinal septa with newly formed fiber bone, as well as the gradual replacement of fiber bone with lamellar bone, is termed internal or histologic remodeling. (32)

Large, irregularly shaped cells with foamy, eosinophilic cytoplasm and one or more nuclei each containing several nucleoli are evenly distributed throughout the entire metaphysis except in the primary spongiosum. These osteoblasts are also seen subperiosteally around the outside of the metaphysis where it diminishes in diameter to meet the diaphysis. This narrowing or funnelization of the metaphysis is termed external or anatomic remodeling.(32)

The functions of the metaphysis therefore, are vascular invasion of the transverse septa at the bottom of the cartilaginous portion of the growth plate, bone formation, and remodeling, both internal and histologic (removal of calcified cartilage bars and replacement of fiber bone with lamellar bone) and external or anatomic (funnelization of the metaphysis).

FIBROUS AND FIBROCARTILAGINOUS COMPONENTS

Encircling the typical long-bone growth plate at its periphery are a wedge-shaped groove of cells, termed the ossification groove, and a ring or band of fibrous tissue and bone, termed the perichondrial ring(Fig. 2-11). Ranvier,(46) the first to describe these structures, concentrated his study on the cells in the groove, which is now named after him. LaCroix(31) studied the perichondrial ring in detail, and this structure is frequently named after him. Although it is true that the ossification groove and the perichondrial ring are simply different parts of the same structure, they do have different functions, and for that reason alone it is advantageous to consider them as separate and distinct entities. These structures will be described first as they are found in the typical long-bone growth plate (distal femur) and then as they exist in a somewhat different form in the femoral capital growth plate.

FIG. 2-11 Photomicrograph of the periphery of the distal femoral growth plate of a 14-day-old rat shows the ossification groove of Ranvier (A) and the perichondrial ring of LaCroix (B). (H&E x loo) (Brighton CT: Clinical problems in epiphyseal plate growth and development, pp 107-113. AAOS Instructional Course Lecture, vol XXIII, p 107. St Louis, CV Mosby, 1974)

The ossification groove contains round to oval cells that, on light microscopy, seem to flow from the groove into the cartilage at the level of the beginning of the reserve zone. For that reason, and since these cells avidly incorporate tritiated thymidine, it appears that the function of the groove of Ranvier is to contribute chondrocytes to the growth plate for the growth in diameter, or latitudinal growth, of the plate.(52) In a recent, definitive study using electron microscopy and autoradiography, three groups of cells were identified in the ossification groove: a group of densely packed cells that seemed to be progenitor cells for osteoblasts that form the bony band in the perichondrial ring; a group of undifferentiated cells and fibroblasts that contribute to appositional chondrogenesis and, hence, growth in width of the growth plate; and fibroblasts amid sheets of collagen that cover the groove and firmly anchor it to the perichondrium of the hyaline cartilage above the growth plate.(57)

FIG. 2-12 Photomicrograph of the periphery of the proximal femoral growth plate of a 14-day-old rat shows the fibrocartilaginous structure that replaces the groove of Ranvier and perichondrial ring in other growth plates. (H&E x 100)

The perichondrial ring is a dense fibrous band that encircles the growth plate at the bone-cartilage junction and in which collagen fibers run vertically, obliquely, and circumferentially.(45) It is continuous at one end with the group of fibroblasts and collagen fibers in the ossification groove and at the other end with the periosteum and subperiosteal bone of the metaphysis. In rodents, rabbits, and dogs, the innermost layer of the perichondrial ring consists of bone that may or may not be attached to the subperiosteal bone of the metaphysis. This cylindrical sheath of bone may not be present in all species at all ages in all growth plates. For instance, it is not present in the proximal femur in the human at any age. ” Whether or not bone is present in the perichondrial ring, there is no doubt that the ring provides mechanical support for the otherwise weak bone-cartilage junction of the growth plate (17,47,52)

Hence the function of the ossification groove is to provide chondrocytes for the growth in width of the growth plate, and the function of the perichondrial ring is to act as a limiting membrane that provides mechanical support to the growth plate.

In the femoral capital growth plate, the functions of the ossification groove and the perichondrial ring are the same as in any typical long-bone growth plate, but the structure of these peripheral tissues is quite different. Instead of a rather distinct ossification groove and perichondrial ring, these two structures are replaced by one structure that consists of fibrocartilage in the area that is occupied by the groove of Ranvier and the perichondrial ring in other growth plates (Fig. 2-12). This structure apparently has the same functions as the groove of Ranvier and the perichondrial ring, that is, to provide for latitudinal growth of the growth plate (top portion of the fibrocartilaginous structure) and to provide mechanical support to the growth plate (remainder of the fibrocartilaginous structure).(17)

SECTION TWO
DIAPHYSEAL BONE FORMATION

ARTHUR W. FETTER

One of the earliest indications that the cartilage model of a long tubular bone is about to be replaced is the appearance of a thin collar (ring or sleeve) of osseous tissue around the middle. The formation of the osseous collar is induced when the cartilage cells in the area mature and hypertrophy, and the matrix they have produced becomes mineralizable. The collar of bone, which represents the first stage in the development of the cortex of the evolving bone, is formed through intramembranous ossification from osteoblasts in the inner or osteogenic layer of the perichondrium. This fibrous tissue layer, because of its location, should be called periosteum. The cortical shell consists of a loosely woven matrix with more cells per unit area than that which occurs in mature bone.

The formation of the periosteal osseous collar is rapidly followed by the extension of vascular buds from the periosteum through the cortical shell into the cartilaginous area. This process is induced by the degeneration and death of cartilage cells. These primitive vessels enter the degenerating cartilage, bringing with them mononuclear cells and mesenchymal elements, which give rise to the chondroclasts, osteoclasts, and osteoblasts. These cells are essential in the process of enchondral ossification and the formation of the hematopoietic marrow of the evolving bone.

As the diaphysis elongates, the cortical shell of bone continues to develop adjacent to the growth plate and remains at, or slightly beyond, the level of the zone of hypertrophied cartilage cells, providing structural support for the cartilaginous epiphysis. This extension of the cortical shell forms a three-dimensional cup and is called Ranvier’s ossification groove (encoche deRanvier). In order to maintain the funnel shape of the bone as it grows in length, remodeling of the metaphysis begins almost as soon as any bone is formed.

During the rapid advance of enchondral ossification toward the epiphyseal ends of the elongating young bone, growth is also occurring subperiosteally in the diaphysis. The periosteum becomes quite thick, and spicules of new bone are deposited more or less perpendicularly between the cambium layer of the periosteum and the original cortical shell. The matrix of the rapidly deposited bone is loosely woven, resembling burlap, and contains many cells per unit area of bone. As cortical growth in the area of the diaphysis slows, osteoblasts line up on the surface of the bone spicules and slowly deposit lamellar bone in the form of an “inlay” into the spaces between the trabeculae. This filling between the trabeculae results in the formation of a solid cortex. At this stage, the cortex consists of a mixture of woven fiber bone with its haphazard fibrillar arrangement and numerous osteocytes, and the lamellar bone with a parallel arrangement of collagen fibers and fewer osteocytes. The inlay bone has an osteonal appearance, but true osteons are formed as refill after osteoclasts have cut a hole in cortical bone. Therefore, the inlay bone does not qualify as true osteonal bone.

SECTION THREE
CORTICAL REMODELING

ARTHUR W. FETTER

Once a cortical surface is formed, layer after layer of bone is deposited on the surface in the form of coarse lamellar bone. Since this bone is not initially deposited along lines of stress, but rather in response to vascular patterns and growth patterns, remodeling must occur. This remodeling is accomplished by osteoclasts, the number and activity of which are influenced by circulatory, metabolic, and mechanical factors.(59) The initial event in remodeling is the removal by osteoclasts of matrix that was previously deposited by osteoblasts. This occurs through the action of a “cutting cone” of osteoclasts, which progresses more or less longitudinally along the developing shaft of the bone. The cutting cone advances along the course of the vessel, producing a resorption cavity (Fig. 2-13, A). Following along behind the cutting cone, osteoblasts become aligned on the walls of the resorption cavity and secrete a layer of mucopolysaccharides on the surface of the cavity, which is referred to as a cement or reversal line. Successive generations of osteoblasts then produce layers of bone that fill in the resorption cavity in centripetal fashion, leaving a small central canal that contains vessels and nerves. This process results in the production of an osteon or haversian system, which consists of the central canals with their blood vessels, canaliculi, and the concentric lamellae of bone (Fig. 2-13, B). The canaliculi contain osteocytic processes during life and radiate from the central canal, thereby interconnecting the osteocytic lacunae. Thus, each haversian system or osteon is a single metabolic unit nourished by the vessel in the central canal, with nourishment proceeding outward through the canaliculi (Fig. 2-14).

FIG. 2-13 (A) Numerous resorption cavities in various stages of refill in cortical bone. Note recently formed resorption cavities (short arrows) and others that are partially filled by osteonal bone formation (long arrows) The dark circumferential bands within the resorption cavities are osteoid seams of the developing osteon. The mineralized section of bone is stained with Goldner’s modified trichrome stain. (B) Mature cortical bone characterized by fully developed osteons with minimal resorptive activity. The mineralized section of bone is stained with Goldner’s modified trichrome stain.

FIG. 2-14 A single osteon characterized by a central canal (C) osteocytic lacunae (O), and osteocytic processes within canaliculi (arrows). The mineralized bone section is stained with basic fuchsin.

FIG. 2-15 Cortical bone consisting of numerous osteons (O) and interstitial fragments (F). Unstained section of mineralized bone.

As cutting cones remodel bone, they do so with a “skew” determined by mechanical stresses. Therefore, the cutting cone may cross osteonal lines, removing portions of several osteons. When these resorption cavities are refilled, portions of the original osteons are left behind. After several waves of such activity, numerous interstitial fragments remain. Since a cement or reversal line is deposited following the formation of the cavity, the interstitial fragments are not directly connected to any haversian blood supply (Fig. 2-15). With the passage of years and many waves of remodeling activity, the number of interstitial fragments becomes greater and greater. Volkmann’s canals course transversely through the cortex, connecting adjacent haversian systems and providing intercommunication between the medullary and the periosteal blood supply. These canals are not surrounded by concentric layers of bone, as are the osteons.

In my searching to figure out how to increase height, the first step was always to figure out how human height and growth happens and how everything begins. I can say with great confidence that after a few months of learning, reading, and studying, I am probably even more confused than when i first began.

My attempt to understand the human body, the endocrine system, and orthopedics is very slow and when I read statements like “your height is determined by your genetics” I find myself getting frustrated because the people who post this comment don’t or can’t go into detail in explaining themselves. All they are doing is repeating the standard point of view, without knowing how to defend this point.

Now, I do agree with these people that the studies and articles written seem to point to the idea that a person’s height is determined mainly by their genetics. However what are the parts that exactly determine the biological genetic pre-programmed maximum height of an individual?

Some people can give more fuzzy logic answer with something like “their race “or ethnicity”, but does that mean that they suggest that their genetics determine their ethnicity and race? If that is true, then doesn’t hat validate the idea that race  has a genetic basis, which is a very un-politically correct point of view.

The study of genetics, hereditary, genes, and such is still a very young area of study. The human genome with its 22,000 genes were mapped out only a few years ago, and we just realized now that it is probably not the genes that determine everything, but the chemical signals around the gene that determine most of our physical characteristics.

So, “What exactly determines the biological genetic pre=programmed maximum height of an individual?”

If I was to guess at this point in my research, I would say the real determinant is the speed of chemical rate and number of receptors and certain hormones/proteins in each individual humans body to process. It seems that even at the most elementary level, the growth plate processes and senescence is determined by mainly the endocrine system and the hormones it has. This is of course assuming that the individual has not been an individual that has a form of congenital, hereditary, or genetic disorder that causes the malfunction and pathology go the normal human growth process.

At some point in the last month I had found an article talking about children and adults who develop into short stature from tumor induced osteomalacia. This post is not going to have anything to do with height increase but is more of a study on the mechanism behind one of the more common causes for short stature. I am hoping that through learning more about dwarfism and the many causes, we can figure out the entire mechanism for human growth.

For us to understnd tumor induced osteomalacia, we first have to study the general form of osteomalacia. Let’s first to a very quick intro on osteomalacia.

From the Wikipedia article on Osteomalacia (HERE)…

Osteomalacia is the softening of the bones caused by defective bone mineralization secondary to inadequate amounts of available phosphorus and calcium, or because of overactive resorption of calcium from the bone as a result of hyperparathyroidism (which causes hypercalcemia, in contrast to other aetiologies). Osteomalacia in children is known as rickets, and because of this, use of the term osteomalacia is often restricted to the milder, adult form of the disease. It may show signs as diffuse body pains, muscle weakness, and fragility of the bones. The most common cause of the disease is a deficiency in vitamin D, which is normally obtained from the diet and/or from sunlight exposure.

Osteomalacia is a generalized bone condition in which there is inadequate mineralization of the bone. Many of the effects of the disease overlap with the more common osteoporosis, but the two diseases are significantly different. There are two main causes of osteomalacia: (1) insufficient calcium absorption from the intestine because of lack of dietary calcium or a deficiency of or resistance to the action of vitamin D; and (2) Phosphate deficiency caused by increased renal losses.[edit]General characteristics

Osteomalacia is derived from Greek: osteo- which means “bone”, and malacia which means “softness”. In the past, the disease was also known as malacosteon and its Latin-derived equivalent, mollities ossium.

Causes

The causes of adult osteomalacia are varied, but ultimately result in a vitamin D deficiency:

• Insufficient nutritional quantities or faulty metabolism of vitamin D or phosphorus
• Renal tubular acidosis
• Malnutrition during pregnancy
• Malabsorption syndrome
• Hypophosphatemia
• Chronic renal failure
• Tumor-induced osteomalacia
• Long-term anticonvulsant therapy
• Coeliac disease

Clinical features

Osteomalacia in adults starts insidiously as aches and pains in the lumbar (lower back) region and thighs, spreading later to the arms and ribs. The pain is symmetrical, non-radiating and is accompanied by sensitivity in the involved bones. Proximal muscles are weak, and there is difficulty in climbing up stairs and getting up from a squatting position.

Due to demineralization bones become less rigid. Physical signs include deformities like triradiate pelvis^[6] and lordosis. The patient has a typical “waddling” gait. However, those physical signs may derive from a previous osteomalacial state, since bones do not regain their original shape after they become deformed.

Pathologic fractures due to weight bearing may develop. Most of the time, the only alleged symptom is chronic fatigue, while bone aches are not spontaneous but only revealed by pressure or shocks.

It differs from renal osteodystrophy, where the latter shows hyperphosphatemia

Biochemical findings

Biochemical features are similar to those of rickets. The major factor is an abnormally low vitamin D concentration in blood serum.

Major typical biochemical findings are:

• The serum calcium is low
• Urinary calcium is low
• Serum phosphate is low except in cases of renal osteodystrophy
• Serum alkaline phosphatase is high

Furthermore, a technetium bone scan will show increased activity.

Radiological appearances include:

Radiographic characteristics

• Pseudofractures, also called Looser’s zones.
• Protrusio acetabuli, a hip joint disorder

Treatment

Nutritional osteomalacia responds well to administration of 10,000 IU weekly of vitamin D for four to six weeks. Osteomalacia due to malabsorption may require treatment by injection or daily oral dosing of significant amounts of vitamin D.

Me: What is to be taken away is that the disorder of Osteomalacia is a general term used to describe the condition that develops from most often Vitamin D and/or Calcium diffeciency. Osteomalacia in children is known as rickets. Rickets in children leads to limbs and bones being bent or twisted, causing bow legs, knock knees, and cranial, pelvic, and spinal deformities. The cause of this disorder is most often from a lifestyle where the person is not getting enough Vitamin D and Calcium. Being out in the sun, taking around 10,000 IU of Vitamin D for up to 8 weeks, and drinking more milk would help keep the bones from loosing more strength  and density. Osteomalacia and Rickets are often found in places which suffer through famine. It is important to note that Calcium creates the crystals that gets embedded into the matrix of the bone giving it its strength from increased density. If the bone matrix can not absorb the Calcium, it is because the lack of Vitamin D that allow the Calcium to be absorbed.

The other major cause of Osteomalacia is phosphate deficiency caused by increased renal losses. This is where we will look into tumor induced osteomalacia

From Wikipedia (Here)…

Tumor-induced osteomalacia, also known as oncogenic hypophosphatemic osteomalacia or oncogenic osteomalacia, is an uncommon disorder resulting in increased renal phosphate excretion, hypophosphatemia and osteomalacia.

Signs and symptoms

Adult patients have worsening myalgias, bone pains and fatigue which are followed by recurrent fractures. Children present with difficulty in walking, stunted growth and deformities of the skeleton (features ofrickets).^[1]

Diagnosis

Biochemical studies reveal hypophosphatemia, elevated alkaline phosphatase and low serum 1, 25 dihydroxyvitamin D levels. Routine laboratory tests do not include serum phosphate levels and this can result in considerable delay in diagnosis.

Pathogenesis

FGF23 (fibroblast growth factor 23) inhibits phosphate transport in the renal tubule and reduces calcitriol production by the kidney. Tumor production of FGF23, frizzled-related protein 4  and matrix extracellular phosphoglycoprotein (MEPE) have all been identified as possible causative agents for the hypophosphatemia.

Causative tumors

Tumor-induced osteomalacia is usually referred to as a paraneoplastic phenomenon, however, the tumors are usually benign and the symptomatology is due to osteomalacia or rickets. A benign mesenchymalor mixed connective tissue tumor (usually phosphaturic mesenchymal tumor and hemangiopericytoma) are the commonest associated tumors. Association with mesenchymal malignant tumors, such asosteosarcoma and fibrosarcoma, has also been reported.^[6] Locating the tumor can prove to be difficult and may require whole body MRI. Some of the tumors express somatostatin receptors and may be located by octreotide scanning.

Differential diagnosis

Serum chemistries are identical in tumor-induced osteomalacia, X-linked hypophosphatemic rickets (XHR) and autosomal dominant hypophosphatemic rickets (ADHR). A negative family history can be useful in distinguishing tumor induced osteomalacia from XHR and ADHR. If necessary, genetic testing for PHEX (phosphate regulating gene with homologies to endopepetidase on the X-chromosome) can be used to conclusively diagnose XHR and testing for the FGF-23 gene will identify patients with ADHR.

Treatment

Resection of the tumor is the ideal treatment and results in correction of hypophosphatemia (and low calcitriol levels) within hours of resection. Resolution of skeletal abnormalities may take many months.

If the tumor cannot be located, treatment with calcitriol (1-3 µg/day) and phosphorus (1-4 g/day in divided doses) is instituted. Tumors which secrete somatostatin receptors may respond to treatment with octreotide. If hypophosphatemia persists despite calcitriol and phosphate supplementation, administration of cinacalcet has been shown to be useful

Me: For me, the major take away of learning about tumor induced osteomalacia for height increase application is that “the FGF23 (fibroblast growth factor 23) inhibits phosphate transport in the renal tubule and reduces calcitriol production by the kidney. ” This is seems to be the main cause of hypophosphatemia

I haven’t really talked about the family of proteins the FGFs but they are critical in the process of cell differentiaton and prolliferation, which is what causes all type sof tissue growth including bone growth.

This will be a rather short post. I was wondering to myself whether I have ever been rejected for anything because of my height. When most people hear the word “rejection” they think only in terms of professional rejection like not getting a job offer or personal rejection like a girl saying no to them for a lack of height. However, there are other types too.

For me personally, my height is actually about average for the 20-30 year old USA male, being in the 5’11”-6’0″ range. Since I am so average in height, People really don’t look at my height as an asset or liability. When they first see me, most people don’t judge me on my size since I look “normal sized”. Not too short, not too tall. Walking in the streets of the average US city, I could blend in with the crowd around me. When I buy the ticket for an economy seat in an airline, I don’t feel that constrined and my knees are not hitting the seat in front of me. In the average 4- door sedan, I feel rather comfortable in it, with the brakes and steering wheel in a reasonable distance from my limbs.

In terms of my professional life, I don’t think I have ever been rejected for a job or school admission from my size. The people who interviewed me were all very professional and looking at my mind and capabilities. If this was some countries which openly practice discrimination on the job for superficial qualities like China or South Korea I would be in big trouble.

I know some people are not accepted into air force school because they are too big to fit in the cockpit of a jet. I know some people are rejected from gymnastics because their big height prevents them from having a lower center of gravity to do the tumbling and flips that are required. Other than that I can’t think of other possible reasons to reject a person professional for being too tall.

In terms of my personal life, I have been in a few relationships and the girls I was with never said much about my height, and sometimes even said that I was “tall” and they thought my height was “good”. I was acceptable to them.

The only time I have ever been rejected was actually at an amusment park. And it wasn’t even for one of those crazy roller coaster where there is a line that says you have to be taller than a cut off point to ride on it. This was a cut off point for a water park and I was rejected from going on it because I was actually taller than the cut off point. To even think about such a thing sounds weird to me. Can I really be too tall and be rejected for something because I was over the height limit?

I guess a part of me realize that I have been rather lucky in life to have grown to the height I do have right now. Am I selfish for wanting more and to be even taller than average?

What if while everyone else around me feels that I have the perfect average height but deep inside I don’t like my height and wish to be taller?

“Have You Ever Been Rejected From Anything Because Of Your Height?”