This has been my first finger progress update for one year:

Here’s the before picture:

You can see a definite increase in the epiphysis of the middle of the fingers.  Looking at the before video the finger was already slightly curved like that.  I don’t know why only the middle of the finger has responded so drastically maybe it involves blood vessels and hypoxia and clamping in the middle is just more efficient at cutting off those blood vessels then the other areas.

Loading regime has been 500 counts of LSJL on each of the three joint regions on the finger for 4 days and then alternate to loading the legs with LSJL.

Maybe the enhanced force relative to the size of the finger than relative to the leg has resulted in more epiphyseal width growth stimulation in the finger than in the leg.  Maybe a larger clamp is needed for the leg.

I believe an increase in finger length can be seen but a different ruler is used.  And the finger appears to be significantly longer than the earlier one even if the ruler was placed at a different point.  I will continue to work on lowering bodyfat percentage to try to make the bone more noticeable.

Here’s a link to a rock climbing thread to someone who had similar growth in the knuckle.  Now I can’t feel his knuckle to compare to mine.  But there are some differences:  The finger does not look inflammed and does not feel inflammed.  I have no finger pain and there is no restriction in joint movement which is typical of bone spurs.  Another key difference is that in his incidence the whole synovial joint area is enlarge whereas in mine it’s just the epiphysis if you look at mine you can see an indentation between the two epiphysis’.  Torwards the bottom of this page on arthritis you can see a picture of bony spurs: This is not consistent with the growth here as the growth is on the lateral ends of the bone rather than the top.

According to Factors influencing osteological changes in the hands and fingers of rock climbers, rock climbing does not increase osteoarthritis incidence and it does increase finger width.  “Analyses of total width and medullary width reveal that bone is being deposited on the subperiosteal surface, but not endosteally.”

Conclusion:  LSJL has a proven, undisputable effect on bone morphology as shown by the dramatic increase in epiphyseal width.  Those are not calluses.  That is bone.  It is likely not bone spurs nor the same sort of adaptation you might get from rock climbing. LSJL has a highly probable effect on increasing finger length that could become more drastic as alterations and honing of technique is made.

ATF6 is activated in response to ER stress.

Transmission of ER stress response by ATF6 promotes endochondral bone growth.

“X-box binding protein1 spliced (XBP1S), a key regulator of the unfolded protein response (UPR), as a bone morphogenetic protein 2 (BMP2)-inducible transcription factor, positively regulates endochondral bone formation by activating granulin-epithelin precursor (GEP) chondrogenic growth factor. Under the stress of misfolded or unfolded proteins in the endoplasmic reticulum (ER), the cells can be protected by the mammalian UPR. However, the influence of activating transcription factor 6 (ATF6), another transcriptional arm of UPR, in BMP2-induced chondrocyte differentiation has not yet been elucidated. In the current study, we investigate and explore the role of ATF6 in endochondral bone formation, focus on associated molecules of hypertrophic chondrocyte differentiation, as well as the molecular events underlying this process.
High-cell-density micromass cultures were used to induce ATDC5 and C3H10T1/2 cell differentiation into chondrocytes. Quantitative real-time PCR, immunoblotting analysis, and immunohistochemistry were performed to examine (1) the expression of ATF6, ATF6α, collagen II, collagen X, and matrix metalloproteinase-13 (MMP13) and (2) whether ATF6 stimulates chondrogenesis and whether ATF6 enhances runt-related transcription factor 2 (Runx2)-mediated chondrocyte hypertrophy. Culture of fetal mouse bone explants was to detect whether ATF6 stimulates chondrocyte hypertrophy, mineralization, and endochondral bone growth. Coimmunoprecipitation was employed to determine whether ATF6 associates with Runx2 in chondrocyte differentiation.
ATF6 is differentially expressed in the course of BMP2-triggered chondrocyte differentiation. Overexpression of ATF6 accelerates chondrocyte differentiation, and the ex vivo studies reveal that ATF6 is a potent stimulator of chondrocyte hypertrophy, mineralization, and endochondral bone growth{ATF6 may increase height, sometimes accelerators of growth increase height sometimes not}. Knockdown of ATF6 via a siRNA approach inhibits chondrogenesis. Furthermore, ATF6 associates with Runx2 and enhances Runx2-induced chondrocyte hypertrophy. And, the stimulation effect of ATF6 is reduced during inhibition of Runx2 via a siRNA approach, suggesting that the promoting effect is required for Runx2.
Our observations demonstrate that ATF6 positively regulates chondrocyte hypertrophy and endochondral bone formation through activating Runx2-mediated hypertrophic chondrocyte differentiation.”

“BMP2 can activate unfolded protein response (UPR)-signaling molecules, such as BiP (binding immunoglobulin protein), CHOP (C/EBP homologous protein), ATF4 (activating transcription factor 4), and IRE1α (inositol-requiring enzyme-1α). ”

“The UPR is divided into three arms, including the PKR-like ER-resistant kinase (PERK), activating transcription factor 6 (ATF6), and IRE1α; the three together act to restrict new protein synthesis and increase the production of chaperones.”

“. BMP2 induces mild ER stress, and then ATF6, as a 90-kDa protein (p90ATF6) in previous non-ER stress environment, is directly converted to a 50-kDa protein (p50ATF6, ATF6a) in ER-stressed cells.  ATF6 undergoes proteolysis and splicing after BMP2 stimulation. ATF6a protein was not detected until day 5 in BMP2-induced chondrocyte differentiation of ATDC5 cells. The expression of collagen X was also immune positive at day 7, indicating that ATF6a expression is prehypertrophic and hypertrophic chondrocyte-specific. The ER stress-induced ATF6 proteolysis occurs in BMP2 stimulation day 5. More significantly, ATF6a expression was 2 days earlier than that of collagen X.”

“ATF6 significantly stimulated chondrocyte hypertrophy, mineralization, and bone length.”

“ATF6 associates with Runx2 in chondrogenesis and ATF6 enhances Runx2-mediated chondrocyte hypertrophy”

This is knee cartilage and not growth plate cartilage but some characteristics may apply.

Michael mentioned Nerve Growth Factor before in a supplement review.

Rac1 mediates load-driven attenuation of mRNA expression of nerve growth factor beta in cartilage and chondrocytes.

“To determine effect of gentle loads applied to the knee on mRNA expression of nerve growth factor, particularly, the active beta subunit (NGFβ) in cartilage and chondrocyte.  Cyclic compressive loads in vivo and fluid flow in vitro were used to determine the mRNA levels. Alteration of Rac1 GTPase as well as effect of salubrinal, a specific inhibitor of eIF2α phosphatase was assessed. Knee loading at 1 N reduced mRNA levels of NGFβ and its low affinity receptor, p75 in cartilage and subchondral bone{This is in contrast to the Zenith Height product which states that NGFB would increase height}. In cartilage, knee loading at 1 N reduced the phosphorylation level of p38 MAPK (p38-p) and activity of Rac1 GTPase. Consistent with in vivo results, fluid flow at 5 and 10 dyn/cm(2) reduced mRNA levels of NGFβ and p75 in C28/I2 human chondrocytes. SB203580, which decreases p38-p, reduced the mRNA levels of NGFβ and p75. Silencing Rac1 by siRNA decreased the levels of p38-p and NGFβ mRNA but not p75. Furthermore, administration of salubrinal reduced FRET-based activity of Rac1 as well as the mRNA levels of NGFβ and p75.”

The authors interest in NGFB is NGFB’s role in causing pain in cartilage.

“the activation of the p75 receptor has been shown to promote neuronal cell death”

“A basal expression level of NGFβ is high in embryos undergoing skeletal morphogenesis and low in mature cartilage.”<-Maybe NGFB is responsible for growing pains?  This would also suggest that NGFB may be positive for height growth.  It’s also possible that NGFB is just a correlation for height growth and not a causal factor.

12 week old mice were used.  Durating of 1 or 3 hours of LSJL was used used and 1 or 3N was used.  In other LSJL studies, typically 0.5N were used for the force but in one study 1N was used.

“lateral loads to the knee were applied for 5 min at 5 Hz with a peak-to-peak force of 1 and 3 N.”

Levels of NGFB were higher for 3 hours than 1 hour but both were lower than control(see figure 1 in linked study).

Loading at 3N increased p38 phosphorylation whereas loading at 1N decreased p38 phosphorylation levels.  Suppressing p38-p levels may increase chondrocyte proliferation whereas increasing p38-p levels may favor differentiation.  p38 has been implicated in chondroinduction and increasing Sox9 levels.

Fluid Flow of 5 dyn per cm^2 decreased p38-phosphorylation wereas other levels 2, 10, and 20 increased it.

“Knee loading induces not only pressure alterations but also pressure driven fluid flow to chondrocytes. Unlike well-studied effects of normal stress on chondrocytes, it has been recently suggested that a consequence of compressive loading is production of hydrostatic pressure as well as fluid flow to cartilage. In osteoarthritis, chondrocytes are exposed to flow shear due primarily to synovial fluid and high amplitude of fluid flow reproduces the hallmarks of osteoarthritis in vitro”

This was admittedly a dissapointing LSJL study but based on how NGF-Beta affects height we can see that there may be a need to use heavier LSJL loads.  Since p38-phosphorylation favors differentiation and heavier loads increased p38-phosphorylation more than medium loads.  Heavy loads may be needed to induce chondro-growth plate induction by LSJL.

Here’s an hypoxia study that may provide insight on p38 and chondroinduction:

Hypoxia promotes chondrogenesis in rat mesenchymal stem cells: a role for AKT and hypoxia-inducible factor (HIF)-1alpha.

“Cartilage is an avascular tissue and thus resides in a microenvironment with reduced oxygen tension. The aim of this study was to examine the effect of a low oxygen environment on MSC differentiation along the chondrogenic route. In MSCs exposed to chondrogenic growth factors, transforming growth factor-beta and dexamethasone, in a hypoxic environment (2% oxygen), the induction of collagen II expression and proteoglygan deposition was significantly greater than that observed when cells were exposed to the chondrogenic growth factors under normoxic (20% oxygen) conditions. The transcription factor, hypoxia-inducible factor-1alpha (HIF-1alpha), is a crucial mediator of the cellular response to hypoxia. Following exposure of MSCs to hypoxia (2% oxygen), HIF-1alpha translocated from the cytosol to the nucleus and bound to its target DNA consensus sequence. Similarly, hypoxia evoked an increase in phosphorylation of both AKT and p38 mitogen activated protein kinase, upstream of HIF-1alpha activation. Furthermore, the PI3 kinase/AKT inhibitor, LY294002, and p38 inhibitor, SB 203580, prevented the hypoxia-mediated stabilisation of HIF-1alpha. To assess the role of HIF-1alpha in the hypoxia-induced increase in chondrogenesis, we employed an siRNA knockdown approach. In cells exposed to HIF-1alpha siRNA, the hypoxia-induced enhancement of chondrogenesis, as evidenced by upregulation of collagen II, sox-9 and proteoglycan deposition, was absent. This provides evidence for HIF-1alpha being a key mediator of the beneficial effect of a low oxygen environment on chondrogenesis.”

The paper mentions ultrasound as being able to stabilize HIF-1.

“rat MSCs undergo chondrogenesis, as evidence by enhanced collagen II expression and proteoglycan deposition, when exposed to TGFβ and dexamethasone in a normoxic environment. When the MSCs were exposed the chondrogenic factors for 2 weeks in normoxia, followed by 1 week in hypoxia (2% oxygen), chondrogenesis was significantly enhanced, demonstrating that a reduced oxygen tension favours differentiation along the chondrogenic route. The hypoxic environment increased HIF-1α nuclear accumulation and its transactivation in an Akt- and p38-dependent manner. ”

“In ATDC5 chondroprogenitor, hypoxia alone favours chondrogenesis, whilst insulin-mediated chondrogenesis is inhibited by hypoxia ”

Thus it is more likely that heavier loads would be beneficial in an LSJL regime due to the effects of p38 phosphorylation.  However, in the LSJL gene expression study and several LSJL lengthening studies 0.5N was used.  Perhaps, the LSJL based lengthening does not involve p38 but rather the ERK pathway.  Sox9 was in fact upregulated in that study while a decrease in p38 phosphorylation tends to decrease Sox9 expression.

Kaempferol levels were elevated in one study after administration of fructus sophorae extract.  Kaempferol is found in foods like strawberries, grapes, apples, etc.

It is important to note that in the following study ATDC5 cells were involved.  They are not like mesenchymal stem cells in that they are already chondrocyte progenitor cells and are primed for chondrogenesis.

Kaempferol Induces Chondrogenesis in ATDC5 Cells through Activation of ERK/BMP-2 Signaling Pathway.

“Endochondral bone formation occurs when mesenchymal cells condense to differentiate into chondrocytes, the primary cell types of cartilage. We investigated whether kaempferol induces chondrogenic differentiation in clonal mouse chondrogenic ATDC5 cells. Kaempferol treatment stimulated the accumulation of cartilage nodules in a dose-dependent manner. Kaempferol-treated ATDC5 cells stained more intensely with alcian blue staining than control cells, suggesting greater synthesis of matrix proteoglycans in the kaempferol-treated cells. Kaempferol induced greater activation of alkaline phosphatase activity than control cells, and it enhanced the expression of chondrogenic marker genes, such as collagen type I, collagen type X, OCN, Runx2, and Sox9{these are a lot of osteogenic genes too}. Kaempferol induced an acute activation of extracellular signal-regulated kinase (ERK) but not c-jun N-terminal kinase or p38 MAP kinase. PD98059, an inhibitor of MAPK/ERK, decreased in stained cells treated with kaempferol. Furthermore, kaempferol greatly expressed the protein and mRNA levels of BMP-2, suggesting chondrogenesis was stimulated via a BMP-2 pathway. Kaempferol has chondromodulating effects via an ERK/BMP-2 signaling pathway and could potentially be used as a therapeutic agent for bone growth disorders.”

Perhaps Kaempferol could be useful for people with existing growth plates as they already have chondroprogenitor cells.

“Cells were treated with kaempferol or insulin for 21 days. ATDC5 cells treated with insulin showed chondrogenic differentiation 7 days after treatment through the condensation of stage cartilage nodules. ATDC5 cells treated with 5 μM of kaempferol showed differentiation similar to the insulin-treated cells, including the development of cartilage nodules “<-So ATDC5 cells are already primed for chondrogenesis with chondroinduction occurring merely with insulin.  Kaempferol however was more chondroinductive than mere insulin.

“phosphorylation of JNK and P38 Kinase did not occur with insulin treatmen. Treatment with 5 μM of kaempferol showed acute activation of ERK kinase after 1.5 h and the phosphorylation of P-38 Kinase was also observed from 1.5 h to 6 h. Similarly, 5 μg/ml of insulin treatment showed activation of ERK kinase and in a similar pattern to kaempferol, suggesting kaempferol has the ability to induce chondrogenic effect via the activation of ERK and P-38 MAPK. Moreover activation of ERK Kinase by Kaempferol and Insulin suggest that Kaempferol can mimic the effects of insulin with regards to activating phosphorylation of the ERK MAP kinase.”<-The phosphorylation of p38 kinase may be responsible for the enhanced chondroinductive effects and any compound that results in the phosphorylation of p38 could have similar chondrostimulatory effects.

“kaempferol affects the synthesis of matrix proteoglycans and the activity of ALP.”

“kaempferol could potentially be used to treat a variety of skeletal diseases, such as dwarfism”<-The authors have more faith in kaempferol than would be inferred from the results of the study.

Perhaps the authors are alluding to the reduction of insulin and replacement of more sources of kaempferol to grow taller during development.  More apples and less bread for taller infants.

There’s no indication that kaempferol could be chondroinductive on adult Mesenchymal Stem Cells however but it could be synergestic with other adult height increase stimulants.

Here’s a patent related to kaempferol:

Nutritional compositions for promotion of bone growth and maintenance of bone health and methods regarding same

“A composition comprising an active ingredient having a therapeutically effective amount of a rosemary plant or rosemary plant extract containing at least one phytochemical having the ability to induce bone morphogenic protein expression.  The phytochemical is selected from the group consisting of eupafolin, carnosol, scutellarein, genkwanin, kaempferol, acacetin and combinations thereof.”

Kaempferol is mostly identified as a BMP-2 stimulant which does have potential height increase effects.

Spinal nociceptive transmission by mechanical stimulation of bone marrow.

“in addition to the periosteum, many unmyelinated calcitonin gene-related peptide-labeled fibers innervate bone marrow.”

“nociceptors in bone marrow are likely to be excited by increased pressure in bone marrow, possibly resulting in activation of pain pathways including the spinal dorsal horn (SDH)”

“mechanical stimulation to bone marrow, which induces an increase in intraosseous pressure, elicits nociceptors located in bone marrow.”

“both electrical stimulation and increase in pressure within bone marrow generate a blood pressure increase that may be indicative of nociceptive activation.”

“An increase in intraosseous pressure has been shown to activate fine-diameter afferent nerve fibers arising from bone marrow, as do irritant and inflammatory agents such as H+and K+ ions and histamine and bradykinin.”

Recreational runners with patellofemoral pain exhibit elevated patella water content.

“Increased bone water content resulting from repetitive patellofemoral joint overloading has been suggested to be a possible mechanism underlying patellofemoral pain (PFP). To date, it remains unknown whether persons with PFP exhibit elevated bone water content. The purpose of this study was to determine whether recreational runners with PFP exhibit elevated patella water content when compared to pain-free controls. Ten female recreational runners with a diagnosis of PFP (22 to 39years of age) and 10 gender, age, weight, height, and activity matched controls underwent chemical-shift-encoded water-fat magnetic resonance imaging (MRI) to quantify patella water content (i.e., water-signal fraction). Differences in bone water content of the total patella, lateral aspect of the patella, and medial aspect of the patella were compared between groups using independent t tests. Compared with the control group, the PFP group demonstrated significantly greater total patella bone water content (15.4±3.5% vs. 10.3±2.1%; P=0.001), lateral patella water content (17.2±4.2% vs. 11.5±2.5%; P=0.002), and medial patella water content (13.2±2.7% vs. 8.4±2.3%; P<0.001). The higher patella water content observed in female runners with PFP is suggestive of venous engorgement and elevated extracellular fluid. In turn, this may lead to an increase in intraosseous pressure and pain.”

It would be interesting if running caused greater patella(kneecap) size and this increase in patella size was intraosseous pressure related.  But I couldn’t find evidence of running increasing patella size.  The change in water content is low so it’s possible that that increase in hydrostatic pressure was not significant enough.  All it would take is one example of running increasing patella size though.

The role of cartilage canals in endochondral and perichondral bone formation: are there similarities between these two processes?

“Cartilage canals are tubes containing vessels that are found in the hyaline cartilage prior to the formation of a secondary ossification centre (SOC). Their exact role is still controversial and it is unclear whether they contribute to endochondral bone formation when an SOC appears. We examined the cartilage canals of the chicken femur in different developmental stages (E20, D2, 5, 7, 8, 10 and 13). To obtain a detailed picture of the cellular and molecular events within and around the canals the femur was investigated by means of three-dimensional reconstruction, light microscopy, electron microscopy, histochemistry and immunohistochemistry [vascular endothelial growth factor (VEGF), type I and II collagen]. An SOC was visible for the first time on the last embryonic day (E20). Cartilage canals were an extension of the vascularized perichondrium and its mesenchymal stem cell layers into the hyaline cartilage. The canals formed a complex network within the epiphysis and some of them penetrated into the SOC were they ended blind{Perhaps we can find a way to recreate cartilage canals?}. The growth of the canals into the SOC was promoted by VEGF. As the development progressed the SOC increased in size and adjacent canals were incorporated into it. The canals contained chondroclasts, which opened the lacunae of hypertrophic chondrocytes, and this was followed by invasion of mesenchymal cells into the empty lacunae and formation of an osteoid layer. In older stages this layer mineralized and increased in thickness by addition of further cells. Outside the SOC cartilage canals are surrounded by osteoid, which is formed by the process of perichondral bone formation. We conclude that cartilage canals contribute to both perichondral and endochondral bone formation and that osteoblasts have the same origin in both processes.”

“Cartilage canals are tubes of vascularized mesenchyme that are present in bones of vertebrates.”

“cartilage canals regress with age in the distal femur of pigs”

“Cartilage canals originate from the perichondrium (p) and penetrate into the reserve zone (rz) of the cartilage matrix.”

“In the chicken femur cartilage canals contain arterioles, venules, capillaries and mesenchymal cells which are embedded in the canal matrix”

“the matrix of the canals contains no type II collagen, whereas the surrounding cartilage matrix of the reserve and the proliferative zone is rich in this type of collagen. Thus, a demarcation between the canals and the surrounding cartilage matrix appears and ultrastructural data clearly show that no epithelium is elaborated around the canals.”

“the perichondrium is composed of an inner layer that has the characteristics of osteoprogenitor cells and an outer fibroblastic layer. Both layers can provide their mesenchymal stem cells, which migrate into and along the cartilage canals. Several cartilage canals penetrate into the SOC and multinucleated chondroclasts resorb the calcified cartilage matrix and hence open the lacunae of hypertrophic chondrocytes.”