Correlation does not imply causation.  Just because the growth plates disappear correlates with the near cessation of longitudinal bone growth does not mean that the disappearance of growth plates causes the cessation of longitudinal bone growth.  Maybe a uniform factor causes both the disappearance of growth plates and cessation of growth.  Maybe the cessation of growth causes the disappearance of growth plates.  May another factor ceases both.

I’m testing the hypothesis that maybe it’s the joints themselves that place the constraint on longitudinal bone growth.  If you look at the above image of a toddlers hands you notice the near absence of joints/knuckles.  One of the main difference between adult and childs bones is that adults have much prominent epiphysis.  LSJL attempts to stimulate that epiphysis in one way. What if the epiphysis itself constrains growth. If you look at the image below by pulling my finger that I’m sort of creating the knuckle gap that’s like the child hand.

So the test is to see if by pulling the finger that we can alleviate the potential constraints on growth.  I can’t do it 24/7 and if it does constrained growth there should only be a need for certain periods of time where growth is unconstrained by the epiphysis.  So I’m going to be pulling my right pinky finger for 15 minutes.  I need time to perform LSJL too.  All my left fingers are longer than my right and there are some images below so if my right pinky becomes longer than my left.

We can only really draw conclusions if this works.  If this works then we can see that it is the epiphysis itself that is the sole constraint on longitudinal bone growth and that by pulling the finger for enough time during the day we allow for growth to occur.  If it doesn’t work then we can’t really say anything.  Maybe I didn’t do it for enough time or maybe you need to stimulate neo-growth plate formation in addition to preventing the epiphysis’ from constraining growth.

If this works it also bodes well for growing taller via spinal height as you can stretch those as well.  However, usually when you stretch in one way you usually compress another and any activity involving the spine is more dangerous due it’s important bodily role.

This may sound crazy.  How can it possibly work?  I just saw a toddlers hands and noticed that gap where joints could be.  Then I pulled my finger and saw the gap sort of made my hand more toddler like.  The logical stretch is that how can you possibly grow without stimulating growth plates.  Well, every single field of science is understudied.  Correlation does not apply causation.  The hypothesis being tested here is:

The epiphysis puts a constraining factor on longitudinal bone growth by pulling the finger apart you allow for release from that factor temporarily allowing for possible new longitudinal bone growth to occur.

I recent did some LSJL measurements and I didn’t have any significant increase in length.  I think the reason for this is that I wasn’t clamping long enough.  During the last few months I’ve been clamping hard so that I stop clamping sooner due to pain and can get it over with.  However, I don’t think that is enough time to build up hydrostatic pressure.  This is contrast to the method I post recently that had a very long clamping time.  I think that my attempt to shortcut the process by getting into more intense clamping faster denied me of results.  Slower clamping also allows for the surrounding muscles and tendons to adapt to the clamping meaning an eventual more intense clamping force before they start resisting.

Given that mesenchymal stem cells can differentiate into chondrocytes via hydrostatic pressure it’s very likely that their is an epithelial intermediary to allow for chondrogenic differentiation and epithelial cells are important to form the resting zone of the growth plate.  LSJL tries to increase hydrostatic pressure.  Although response to hydrostatic pressure may be dependent on cell matrix interactions.

I do have strong faith in LSJL given wingspan increase results and possible finger length increase.  I performed LSJL on my right finger.  My right finger appeared longer than my left.  I got X-rays and after exhaustive analysis all my left finger bones were in fact longer except for my right metacarpal.  And upon observation most of my left hand bones do appear to be longer than my right.  Thus, the difference in size between the right and left metacarpal is very likely due to LSJL.

So now I will be performing LSJL on my left index finger to try to get the left metacarpal longer than my right and I will be ramping up the clamping of other joints that I perform LSJL on more slowly and longer duration.

Update 12/10/2015: The Twitter Account of EpiBone actually wrote a response back to our tweet of its original reply. Technically, they did not confirm it. We corrected that error. My personal interpretation of what they said, if the reply is real, is that the representative from EpiBone said the theoretical tissue engineering is possible. We might have read too far into that message. They technically did not confirm my hypothesis. Semantics 🙂

Sometimes I have to give a lot of credit to the readers and this one goes to someone who actually did something. They contacted the people at EpiBone and asked a simple question.

What I proposed in previous posts about the research (and application) Dr. Warren Grayson and company was working on, and how it applies to making people with no growth plates taller, was I telling the truth?

Someone named BD wrote and got a reply. Like I said, it would take years. The answer is always “years into the future”. How many years? Me being an optimist, I say 20-25 years. However, biomedical research based companies who were started by Ph.D/Academics from universities are usually very cautious and slow. More likely, assuming the rate of technological growth, It would be another 40 years or so.

This study is huge because we can get adult epithelial cells to potentially form new growth plates.  Since the resting zone is composed of mainly endothelial-like cells and the resting zone is the foundation of the growth plate.  Understanding how to transition adult mesenchymal stem cells into endothelial cells may be the basis for forming a new growth plate.

Epithelial-mesenchymal transition and mesenchymal-epithelial transition response during differentiation of growth-plate chondrocytes in endochondral ossification.

“For linear longitudinal bone elongation, the stem-like progenitor chondrocytes distributed in resting zone (RZ) of growth plate have a capacity to differentiate towards the spindle chondrocytes in proliferative zone (PZ), then towards the columnar and tightly adjacent chondrocytes in hypertrophic zone (HZ). We hypothesized this process of endochondral ossification with cells morphological change was occurred along with the inter-conversion between epithelial to mesenchymal cell types. Consistent with this hypothesis, the chondrocytes highly expressed mesenchymal-like biomarkers and loss of epithelial surface markers in PZ, while converse in RZ and HZ of the growth plate in mice distal tibia in vivo.  The 4-week old male and female mice were treated with estradiol cypionate or oxandrolone, then investigated the response of epithelial- and mesenchymal biomarkers, and demonstrated that estrogen blocked the EMT process from RZ to PZ while androgen promoted MET from PZ to HZ. Our observations supported the hypotheses that the growth plate firstly go through EMT from RZ to PZ, then MET process from PZ to HZ during the epiphyseal fusion. Our results could interpret the different roles of estrogen and androgen in growth plate cartilage [undergoing] endochondral ossification.”

In Epiphelial to Mesenchymal Cell Transition, cells lose cell-cell adhesion and cell polarity properties to become more migratory mesenchymal cells.  Since the growth plate firstly grows via Epipthelial to Mesenchymal Cell Transitiation at the RZ to PZ that is the most important stage for us to focus on as that causes the formation of the growth plate and the formation of the growth plate would be a great help in growing taller.  However, the cell condensation stage to establish the resting cell zone should first require epithelial cell types as cell to cell adhesion would be needed.

“Multiple tissues differentiation and organs formation in embryonic development arise from a
series of conversion from epithelial to mesenchymal cells, through epithelial to mesenchymal
transition (EMT) or mesenchymal to epithelial transition (MET). In primary EMT process,
the primitive epithelia lose their characterization of rounded shape, sequential arrangement and compact junctions to convert a population of spindle, loosely organized but motile mesenchymal cells{hydrostatic pressure may help organize the stem cells and change the structure of these cells} for gastrulation formation and neural crest migration. Then, after a transient epithelial structure condensation through MET, these population in notochord, somites, somatopleure and splanchnopleure derived from mesoderm generate mesenchymal cells which have ability to differentiate into specific cells types of diverse tissues via the secondary EMT”

” the neural crest cells migrate to somites of mesoderm following stereotyped pathways and undergo a secondary EMT to generate mesenchymal condensation.  These mesenchymal cells differentiate into osteoprogenitors for intramembranous ossification and chondrocytes for endochondral ossification. ”

” Pluripotent stem cells exhibit epithelial characteristics, down-regulate the epithelial markers such as Cdh1, Cldn6, Epcam and enhance the mesenchymal markers including Snai1/2, Zeb1,
CtnnbIP1″

” estrogen administration maintains the epithelial type genes expression in growth plate particularly in RZ implies that estrogen appears to block EMT process.”

“Not like human or rabbit, the expression of estrogen receptors within HZ of growth plate in mice and rat was extremely low until at the last time point prior to epiphyseal fusion, which also
reflects the less effect of estradiol cypionate to in the HZ in our study. Conversely, Androgen
effectively promotes EMT for  chondrocytes differentiation”

” estrogen may interdict TGF-beta, then further repress Smad3 expression, so that
postpone chondrocytes differentiation via EMT blocking. ”

“Androgen is determined to promote EMT for differentiation. However, androgen improves Smad3 expression but appears to have no response to SIS3, which indicates that androgen may participate in other pathways rather than TGF-beta/Smad3.”

” A notable presence of growth plate was observed in distal tibia of the 4-week but not in 16-week old mice”<-Note that LSJL has worked in 16-week old mice.  Although in the LSJL study they used Sprauge -Dawley rats in contrast to outbred ICR mice.

” The mRNA level of epithelial markers including Cdh1, Cldn6, Col4a1, Krt19, Lamc1 expressed in RZ and HZ were significantly higher than in PZ while the mesenchymal markers such as Acta2, Ctnnb1, Smad3, displayed the converse tendency. The results suggested that a process of EMT occurred in the programming of RZ towards PZ and MET in PZ towards HZ.”

Here’s the 16-week old growth plate, still present but weak:

Epithelial cells may already exist in adult bone marrow.

Epithelial cells in bone marrow: do they matter?

“epithelial-like cells can be detected in the bone marrow of many patients not known to have cancer. ”

Inducing a mesenchymal to epithelial transition would be difficult as I haven’t found any studies of it occuring due to physiological stimuli.  Another possibility though would be to have a growth plate without a resting zone as the proliferative zone consists mainly of mesenchymal cells.  The viability of this depends on the viability of a growth plate without a resting zone.  The resting zone may play a role in growth plate orientation which makes sense as epithelial cells tend to be involved in cell polarity and cell adhesion.

Here’s a diagram of the mesenchymal-epithelial transition:

LSJL upregulates Pcdhb2(protocadherin beta 2), Cdh13, Ctnna3, Fat1(a cell adhesion model).  It downs regulates protocadherin subfamily A, 4(Pcdhga4), AK002616(a miscellaneous Cadherin related protein), Celsr2, Cdh15, Cdh11.  So LSJL has the definite potential to affect the mesenchymal-epithelial transition although how isn’t clear as it affects a lot of related genes but not in a clear pattern

For the other parts LSJL downregulates Cldn13, Dsp(Desmoplakin isoform 1, the downregulation of this gene suggests that LSJL likely encourages the epithelial to mesenchymal transition but that doesn’t mean that it doesn’t encourage the mesenchymal to epithelial transition as well), and upregulates a gene related to Cldn19, Muc3.  It also downregulates an anti-mucin gene.

This diagram mentions the reverse markers:

Here’s another diagram:

According to Actin stress fibres and cell-cell adhesion molecules in tendons: organisation in vivo and response to mechanical loading of tendon cells in vitro.

“Tendons consist of parallel longitudinal rows of cells separated by collagen fibres. The cells are in intimate contact longitudinally within rows, and laterally via sheet-like lateral cell processes between rows. At points of contact, they are linked by gap junctions. Since tendons stretch under load, such cell contacts require protection. Here we describe the organisation of the actin cytoskeleton and actin-based cell-cell interactions in vivo and examine the effect of cyclic tensile loading on tendon cells in vitro. Cells within longitudinal rows contained short longitudinally running actin stress fibres. Each fibre was aligned with similar fibres in the cells longitudinally on either side, and fibres appeared to be linked via adherens junctions. Overall, these formed long oriented rows of stress fibres running along the rows of tendon cells. In culture, junctional components n-cadherin{this increase is actually not good news for creation of epithelial cells as this is a mesenchymal marker} and vinculin and the stress fibre component tropomyosin increased in strained cultures, whereas actin levels remained constant.  (1) cells are linked via actin-associated adherens junctions along the line of principal strain; and (2) under load, cells appear to attach themselves more strongly together, and assemble more of their cytoplasmic actin into stress fibres with tropomyosin. Cell-cell contacts are protected during stretch, and also that the stress fibres, which are contractile, may provide an active mechanism for recovery from stretch. In addition, stress fibres are ideally oriented to monitor tensile load and thus may be important in mechanotransduction and the generation of signals passed via the gap junction network.”

So according to this in response to load cells may establish more cell-cell contact characteristic of epithelial cells.

Mechanism of the Mesenchymal–Epithelial Transition and Its Relationship with Metastatic Tumor Formation

“epithelial characteristics were dramatically associated with increased bone and soft-tissue colonization after intracardiac or intratibial injection.”

“Multiple complex signaling systems are required for the induction of EMT and are also closely related with MET. The FGFR2 gene, which is located at human chromosome 10q26, encodes for FGFR2b and FGFR2c isoforms due to alternative splicing and mutually exclusive use of exon IIIb or exon IIIc. FGFR2b primarily binds FGF10 and FGF7 and is the isoform of choice in epithelial cells, whereas FGFR2c binds FGF2 and is mainly expressed in cells of mesenchymal origin. FGF/FGFR2 signaling governs the EMT that is required for organogenesis in mouse embryos.”

“expression of FGFR2b induced MET [induced cancer in one instance]”

“As for the regulation of FGFR2 isoforms’ alternative splicing, a highly conserved GCAUG element was shown to be required for efficient exon IIIb activation. Afterward, Fox protein family members, especially Fox-2, were shown to regulate the FGFR2 exon choice, and this regulation was absolutely dependent on the GCAUG elements present in the FGFR2 pre-mRNA. Fox-2 induced the FGFR2c to FGFR2b switch, accompanied by molecular and morphological changes consistent with MET”

“2 paralogous epithelial cell type–specific RNA binding proteins, Rbm35a and Rbm35b, which are essential regulators of FGFR2 splicing. Ectopic expression of either protein in cells that express FGFR2c caused a switch in endogenous FGFR2 splicing to the epithelial isoform”<-Note it’s FGFR3 that’s typically associated with dwarfism.

EMT and MET as paradigms for cell fate switching

“Cell fate determination is a major unsolved problem in cell and developmental biology. The discovery of reprogramming by pluripotent factors offers a rational system to investigate the molecular mechanisms associated with cell fate decisions. The idea that reprogramming of fibroblasts starts with a mesenchymal-epithelial transition (MET) suggests that the process is perhaps a reversal of epithelial to mesenchymal transition (EMT) found frequently during early embryogenesis. As such, we believe that investigations into MET-EMT may yield detailed molecular insights into cell fate decisions, not only for the switching between epithelial and mesenchymal cells, but also other cell types.”

“In any given animal tissue, one may find two very common cell types: the epithelial cells that line the surface of a tissue or organ and mesenchymal cells that are embedded in the three-dimensional matrix. “<-Growth plate cells line the bone matrix.

“the epithelial cells are attached to the basement membrane, establish an apical–basal axis of polarity, and communicate with each other through the gap junction. Across and underneath the basement membrane, there is the stroma made of the three-dimensional extracellular matrix synthesized by the resident mesenchymal or stromal cells.”

“Inside the nuclei, Snail genes are considered as the most important downstream targets of the nodal-SMAD2/3 pathway during gastrulation. The Snails may in fact be the guardians of the mesenchymal phenotype by activating mesenchymal genes and suppressing epithelial genes. Indeed, Snails have been shown to down-regulate E-cadherin effectively, which is one of hallmarks for epithelial cells. Snail-deficient embryos could not proceed through gastrulation and form mesodermal cells as they could not down-regulate the expression of E-cadherin in the primitive streak. It is generally recognized that the embryonic EMT process is orchestrated and maintained through the collaboration of extracellular signals and intracellular transcription factors.”

When I first started writing on the website, I remember that people were talking about this supplement combination which was supposed to help you grow taller. M.E.N.S.

That was the acronym used for sleep, exercise, niacin, and melatonin. I wanted to talk about melatonin.

I recently started to take melatonin just to help me sleep and I remembered that I never really did much research on Melatonin. A quick Google Search on the link between melatonin and the possibility that it can help you grow taller reveals many of the older posts written maybe 4–7 years ago, derived from the now dead GrowTallForum.com website.

People believed in this supplement combination. Melatonin was promoted a lot by people of that old forum because the thinking was that since it helps you sleep, and growth hormones are primarily released when you are sleeping, melatonin would mean you have a greater chance of having growth hormones being pushed into your system.

I looked at the link. Is there something there?

I refer to 7 studies, some of them recently published just in 2014.

• Increased melatonin concentrations in children with growth hormone deficiency.
• Geographical Distribution of Adolescent Body Height with Respect to Effective Day Length in Japan: An Ecological Analysis
• Melatonin enhances chondrogenic differentiation of human mesenchymal stem cells.
• Effect of Melatonin on the Proliferation and Differentiation of Chondrocytes from Rat Vertebral Body Growth Plate In Vitro
• Melatonin Modulates the Proliferation and Differentiation of Human Growth Plate Chondrocytes: Poster #311{Tyler-What’s notable about this study is that it states that Growth Plate Chondrocytes express two melatonin receptors MT1 and MT2.  It states that Melatonin stimulates the differentiation of GPCs but inhibits proliferation which could increase height as differentiation is more important than proliferation for height}
• Melatonin combined with treadmill exercise suppresses aberrant chondrocyte behavior in osteoarthritic cartilage via TGF-β1 upregulation (LB834)
• Abnormal Response of the Proliferation and Differentiation of Growth Plate Chondrocytes to Melatonin in Adolescent Idiopathic Scoliosis

The 3rd study suggests that Melatonin does have this ability to turn MSCs into the chondrogenic lineage. Other sources (#7) says that for the growing child, over-expression of melatonin in the system can cause abnormal chondrocyte growth. It turns out that young kids who have idiopathic scoliosis actually have longer bones (vertebral column and arm length) than their peers. The curvature of the vertebral is because the anterior region of the vertebral is growing faster than the posterior region.

Out of all of the 7 studies, I felt that study #1 was the most insightful.

Short stature is most often caused by 2 ways.

1. Idiopathic Short Stature (ISS)
2. Growth Hormone Deficiency (GHD)

It seems that for children who suffer from GHD, they have GHD because of the overexpression of melatonin.

This means that based on this 1 studies, when we generalize the conclusion, it seems that having too much melatonin in the child’s system is bad for their height. However, this condition is something that can be medically treated, unlike ISS, which most family doctors would say makes the kids “genetically predisposed to be short later in life”.

So while MSCs might be helped slightly by Melatonin, too much Melatonin is a bad thing. Referring to study #5, the conclusion states the following for peri-pubertal children. – “These findings indicated that melatonin could inhibit the proliferation and stimulate differentiation of GPC (Growth Plate Chondrocytes) in human”{Tyler-Actually this could be a thing for a height growth as peak chondrocyte hypertrophy is more important than chondrocyte proliferation for peak height growth}

Taking Melatonin does not work. Try to figure out another type of supplement to take to sleep easier.