Prx1 seems to be a very promising target for height increase as it seems to have targets early in development.  Unfortunately, I couldn’t find any Prx1 stimulating substances but hopefully you can?  Srx1 is involved in the repair of Prx1 so that could be another target as well.

Regulatory divergence modifies limb length between mammals

“Natural selection acts on variation within populations, resulting in modified organ morphology, physiology, and ultimately the formation of new species. Although variation in orthologous proteins can contribute to these modifications, differences in DNA sequences regulating gene expression may be a primary source of variation. We replaced a limb-specific transcriptional enhancer of the mouse Prx1 locus with the orthologous sequence from a bat. Prx1 expression directed by the bat enhancer results in elevated transcript levels in developing forelimb bones and forelimbs that are significantly longer than controls because of endochondral bone formation alterations. Surprisingly, deletion of the mouse Prx1 limb enhancer results in normal forelimb length and Prx1 expression, revealing regulatory redundancy. These findings suggest that mutations accumulating in pre-existing noncoding regulatory sequences within a population are a source of variation for the evolution of morphological differences between species and that cis-regulatory redundancy may facilitate accumulation of such mutations.”

“One developmental control gene known to promote limb skeletal elongation is Prx1, also called MHox or Prrx1. Prx1 is a paired-related homeobox gene expressed in somites, craniofacial mesenchyme, and limb mesoderm during mouse development”

“the forelimbs of Prx1BatE/BatE mutants are on average ∼6% longer than their wild-type littermates at E18.5 ”

“The forelimbs of Prx1-null homozygotes are ∼12.5% shorter than controls at E18.5”

“average mutant long bones express ∼70% more Prx1 than wild-type siblings”

“Long bone chondrocyte proliferation is elevated by ∼6% at E15.5 in Prx1BatE/BatE mutants.”

“[The Prx1 induced] limb elongation arises at stages of mouse gestation when Prx1 expression is limited to the perichondrium of the developing limb skeletal elements. It is known that the perichondrium is an important regulator of endochondrial bone growth”<-Could this be related to the zone of Ranvier which should be connected to the perichondrium?  Since the zone of Ranvier is linked to an earlier developmental state of the growth plate it could mean that Prx1 could be helpful in inducing neo growth plates.

According to this grant, Prx1 inhibits bone formation so it favors an earlier developmental state overall.

Prx1-Expressing Progenitor Primary Cilia Mediate Bone Formation in response to Mechanical Loading in Mice

“Increases in mechanical loading can enhance the addition of new bone, altering geometry and density such that bones better withstand higher forces. Bone-forming osteoblasts have long been thought to originate from progenitors, but the exact source is yet to be identified. Previous studies indicate osteogenic precursors arise from Prx1-expressing progenitors during embryonic development and adult fracture repair. However, it is unknown whether this cell population is also a source for mechanically induced active osteoblasts. We first identified that Prx1 is expressed in skeletally mature mouse periosteum, a thin tissue covering the surface of the bone that is rich in osteoprogenitors. We then traced Prx1 progenitor lineage using a transgenic mouse model carrying both a Prx1-driven tamoxifen-inducible Cre and a ROSA-driven lacZ reporter gene. Cells that expressed Prx1 when compressive axial loading was applied were detected within the cortical bone days after stimulation, indicating osteocytes are of Prx1-expressing cell origin. In addition, we evaluated how these cells sense and respond to physical stimulation in vivo by disrupting their primary cilia, which are antenna-like sensory organelles known to enhance mechanical and chemical signaling kinetics. Although Prx1-driven primary cilium disruption did not affect osteoblast recruitment to the bone surface, the relative mineral apposition and bone formation rates were decreased by 53% and 34%, respectively. Thus, this cell population contributes to load-induced bone formation, and primary cilia are needed for a complete response. Interestingly, Prx1-expressing progenitors are easily extracted from periosteum and are perhaps an attractive alternative to marrow stem cells for bone tissue regeneration strategies.”

“periosteum, which surrounds bones and is rich in progenitor cells known to preferentially differentiate towards the osteogenic lineage”

“physical stimulation activates and encourages osteogenic differentiation of progenitors within the periosteum.”

“One potential mechanism by which progenitor cells may become mechanically activated is through the primary cilium. Primary cilia are antenna-like organelles that extend from the cell surface and serve as signaling microdomains.”

“osteogenic response to fluid shear is lost when periosteal progenitor primary cilia are disrupted in vitro”

“Prx1-expressing cells become embedded osteocytes in response to physical loading and this mechanism requires the primary cilium.”<-if Prx1 enhances longitudinal bone growth and Prx1 mainly effects on chondrogenic cells maybe there are non chondrogenic ways to enhance longitudinal bone growth.

If we can figure out how to grow via articular cartilage that will be a lot easier than to try to create neo-growth plates.

Spatial Regulation of Gene Expression During Growth of Articular Cartilage in Juvenile Mice.

“In juvenile mammals, the epiphyses of long bones grow by chondrogenesis within the articular cartilage. A bWe used laser-capture microdissection to isolate chondrocytes from the superficial, middle, and deep zones of growing tibial articular cartilage in the 1-wk old mouse and then investigated expression patterns by microarray. To identify molecular markers for each zone of the growing articular cartilage, we found genes showing zone-specific expression and confirmed by real-time PCR and in situ hybridization.Bioinformatic analyses implicated ephrin receptor signaling, Wnt signaling, and BMP signaling in the spatial regulation of chondrocyte differentiation during growth. Molecular markers were identified for superficial (e.g. Cilp, Prg4), middle (Cxcl14, Tnn), and deep zone (Sfrp5, Frzb). Comparison between juvenile articular and growth plate cartilage revealed that the superficial-to-deep zone transition showed similarity with the hypertrophic-to-resting zone transition{This is interesting, the study speculates that both the resting zone and deep zone may come from the same pool of epiphyseal chondrocytes}.ConclusionsLaser capture microdissection combined with microarray analysis identified novel signaling pathways that are spatially regulated in growing mouse articular cartilage and revealed similarities between the molecular architecture of the growing articular cartilage and that of growth plate cartilage.”

“While cell proliferation occurs sparingly in adult articular cartilage, it is much more common in juvenile articular cartilage. Growth of the articular cartilage reportedly occurs appositionally from the articular surface, suggesting that the SZ may contain actively dividing chondrocytes, or a progenitor cell population that is capable of generating new chondrocytes”<-these properties could be exploited to induce new longitudinal bone growth

“DZ[Deep Zone Articular Cartilage] expressed a high level of Wnt5b, which promotes chondrogenesis and inhibits hypertrophy ”

The development of articular cartilage: evidence for an appositional growth mechanism

“It is well-established that cartilage grows by a combination of matrix secretion, cell hypertrophy and cell proliferation. The extent to which this growth is by appositional, as opposed to interstitial mechanisms, however, remains unclear. Using the knee joints of the marsupial Monodelphis domestica to study cartilage growth, we have combined an immunohistochemical study of the TGF-β family of cartilage growth and differentiation factors between 30 days postpartum to 8 months, together with a stereological analysis of cartilage morphology during growth. Furthermore, to gain an insight into the generation of the characteristic zones within cartilage, we have examined the effects of intra-articular administration of bromodeoxyuridine, an agent that is incorporated into DNA during cell division and blocks further cell cycling. During early growth, TGF-β2 and -β3 were widely expressed but TGF-β1 was less so. After the formation of the secondary centre of ossification, all isoforms became more restricted to the upper half of the tissue depth and their distribution was similar to that previously described for IGFs, and PCNA-positive cells. Stereological analysis of tissue sections from the femoral condylar cartilage at 3 and 6 months showed that there was a 17% increase in total cartilage volume but a 31% decrease in cell density on a unit volume basis. Finally, cell-cycle perturbation with BrDU, which was injected into the knee joints of 3-month-old animals and analysed 1 and 4 months post-injection, revealed that the chondrocytes occupying the transitional zone were depleted 1 month post-injection, resulting in thinning of the articular cartilage. This effect was reversed 4 months post-injection. Immunohistochemical analysis revealed that BrDU-treatment altered the expression patterns of all TGF-β isoforms, with a marked reduction in labelling of TGF-β1 and -β3 isoforms in the upper half of the cartilage depth. Overall, the data lends further support to the notion of articular cartilage growing by apposition from the articular surface rather than by interstitial mechanisms.”

Articular cartilage and joint development from embryogenesis to adulthood

“Within each synovial joint, the articular cartilage is uniquely adapted to bear dynamic compressive loads and shear forces throughout the joint’s range of motion.”

“Early studies suggested that a region of proliferating cells “subjacent to the gliding surface of the joint” was responsible for interstitial growth of articular cartilage and increasing thickness of the articular surface. In this same study, Mankin and collaborators found that proliferation continued within deeper regions of the tissue and adjacent to the calcified cartilage, but ceased within the sub-superficial zone at later stages of postnatal growth. The presence of these two proliferative cell regions was confirmed by tritiated thymidine incorporation in the articular cartilage of immature rabbits. Later, Archer and collaborators confirmed the presence of a proliferative cell region in the superficial zone, suggesting that these cells were primarily responsible for the appositional growth and thickening of the articular cartilage postnatally”

“lateral expansion of the articular surface could be attributed to proliferation of cells within the superficial zone that would also give rise to daughter cells in a more rapidly proliferating cell population in the deeper zones leading presumably to vertical tissue growth.”

“In the growth plate, tremendous increases in chondrocyte volume contribute greatly to lengthening of long bones”

“chondrocyte volume in the middle and deep layers increased by over 8 fold from birth to 2 months of age, while overall decreases in cell density reflecting an increase in extracellular matrix production occurred during this same period.”

Hydrostatic pressure is a force we can manipulate via mechanical stimulation.

Hydrostatic pressure promotes the proliferation and osteogenic/chondrogenic differentiation of mesenchymal stem cells: The roles of RhoA and Rac1.

“Hydrostatic pressure can serve as an active regulator for bone marrow mesenchymal stem cells (BMSCs). [We investigate the roles] of cytoskeletal regulatory proteins Ras homolog gene family member A (RhoA) and Ras-related C3 botulinum toxin substrate 1 (Rac1) in hydrostatic pressure-related effects on BMSCs. Hydrostatic pressure promoted cell cycle initiation in a RhoA- and Rac1-dependent manner. RhoA played a positive and Rac1 displayed a negative role in the hydrostatic pressure-induced F-actin stress fiber assembly. RhoA and Rac1 play central roles in the pressure-inhibited ERK phosphorylation, and Rac1 but not RhoA was involved in the pressure-promoted JNK phosphorylation. Pressure promoted the expression of osteogenic marker genes in BMSCs at an early stage of osteogenic differentiation through the up-regulation of RhoA activity. Pressure enhanced the expression of chondrogenic marker genes in BMSCs during chondrogenic differentiation via the up-regulation of Rac1 activity. RhoA and Rac1 are critical to the pressure-induced proliferation and differentiation, the stress fiber assembly, and MAPK activation in BMSCs.”

“Hydrostatic pressure applications are methods of applying mechanical loading that mimics the compressive forces borne by cartilage in a joint cavity“<-So we should be able to apply such mechanical load ourselves but in the bone rather than the cartilage to encourage a neo-ectopic growth plate.

“the activities of Rho GTPase signaling molecules are closely related to the differentiation and the fate of BMSCs.”

“the activation of the RhoA pathway and the inhibition of the Rac1 pathway under hydrostatic pressure promoted the assembly of the F-actin cytoskeleton, whereas the inhibition of the RhoA pathway and the activation of the Rac1 pathway blocked the F-actin cytoskeleton assembly.”

“the down-regulation of RhoA activity and/or pressure significantly blocked the phosphorylation of ERK1/2″<-LSJL increases ERK1/2 phosphorylation.

“RhoA activation inhibited the pressure-induced down-regulation of P-ERK1/2 expression and that RhoA played an important role in the regulation of ERK1/2 phosphorylation upon pressure stimulation.”

“A combination of decreased RhoA activity and pressure stimulation (P/RhoA − group) achieved the maximum expression of the chondrogenic marker genes in BMSCs{So we have to find a way to decrease RhoA levels in the bone}. After two weeks of chondrogenic induction, the expression levels of the chondrogenic genes in the P/RhoA + group were significantly reduced compared with those of the P group. The up-regulation of RhoA antagonized the promoting effect of pressure on the chondrogenic differentiation of the BMSCs{So how do we downregulate RhoA?}. After 4 weeks of chondrogenic induction, the expression levels of Sox-9, Aggrecan and Col II in the RhoA −, P and P/RhoA − groups were significantly higher than those of the control group ”

” pressure inhibited ERK phosphorylation, suggesting that the induction of cell cycle initiation by pressure may not require a modulation of the cyclin D concentration, which involved the regulation of ERK activity through the LIMK protein.”

“pressure promoted the phosphorylation of JNKs but not ERKs in the BMSCs.”

“the damage to the cytoskeletal structure and the inhibition of ROCK activity induced rounded cell morphologies and promoted the expression of chondrogenic marker genes in the BMSCs“<-Maybe hydrostatic pressure will induce more cytoskeletal damage over time and more chondrogenic differentiation will be induced naturally.

“Hydrostatic pressure regulates cell cycle initiation through both the RhoA/Rock and the Rac1 signaling pathways. At the same time, the mechanical stimulation promoted cytoskeletal assembly in BMSCs through the up-regulation of RhoA/ROCK activities, and activation of the JNK1/2 pathway by down-regulation of Rac1 activity. Hydrostatic pressure could also enhance expression of marker genes for early osteogenic differentiation through the up-regulation of RhoA activation or enhance the expression of chondrogenic marker genes in BMSCs during chondrogenic differentiation via the up-regulation of Rac1 activity ”

According to Flavoprotions: Advances in Research and Application: 2011, egf is a stimulator of Rac1.

There are several skin applicators of EGF but I couldn’t find any oral.
I’m not sure if applying it to the skin near the bone/joint region would work in stimulating Rac1 and I’m not sure if ingesting a product meant for the skin is safe nor if it will stimulate any desired region.  But the study suggests Rac1 versus RhoA is a key cellular distinction for osteoblasts versus chondrocytes.  And since there is as yet no RhoA inhibitor(but it’s being investigated due to cancer applications), stimulation of Rac1 via EGF is a worthwhile path to go down.  By encouraging chondrogenesis versus osteogenesis in the bone, it would be easier to great a neo-growth plate.

Rac1 promotes chondrogenesis by regulating STAT3 signaling pathway. has a possible suggestion of how STAT3 could also promote chondrogenesis,

“The small GTPase protein Rac1 is involved in a wide range of biological processes including cell differentiation. Previously, Rac1 was shown to promote chondrogenesis in micromass cultures of limb mesenchyme. However, the pathways mediating Rac1’s role in chondrogenesis are not fully understood. This study aimed to explore the molecular mechanisms by which Rac1 regulates chondrogenic differentiation. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was increased as chondrogenesis proceeded in micromass cultures of chick wing bud mesenchyme. Inhibition of Rac1 with NSC23766, janus kinase 2 (JAK2) with AG490, or STAT3 with stattic inhibited chondrogenesis and reduced phosphorylation of STAT3. Conversely, overexpression of constitutively active Rac1 (Rac L61) increased phosphorylation of STAT3. Rac L61 expression resulted in increased expression of interleukin 6 (IL-6), and treatment with IL-6 increased phosphorylation of STAT3. NSC23766, AG490, and stattic prohibited cell aggregation, whereas expression of Rac L61 increased cell aggregation, which was reduced by stattic treatment. Rac1 induces STAT3 activation through expression and action of IL-6. Overexpression of Rac L61 increased expression of bone morphogenic protein 4 (BMP4). BMP4 promoted chondrogenesis, which was inhibited by K02288, an activin receptor-like kinase-2 inhibitor, and increased phosphorylation of p38 MAP kinase. Overexpression of Rac L61 also increased phosphorylation of p38 MAPK, which was reduced by K02288. These results suggest that Rac1 activates STAT3 by expression of IL-6, which in turn increases expression and activity of BMP4, leading to the promotion of chondrogenesis.”

So BMP4, STAT3, and IL6 are all potential targets to induce chondrogenesis.

Contribution of the Interleukin-6/STAT-3 Signaling Pathway to Chondrogenic Differentiation of Human Mesenchymal Stem Cells.

“Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into chondrocytes. Articular cartilage contains MSC-like chondroprogenitor cells, which suggests their involvement in the maintenance of cartilage homeostasis by a self-repair mechanism. Interleukin-6 (IL-6) is a cytokine [which is] produced by MSCs in a steady manner and in large quantities. The purpose of this study was to investigate the involvement of IL-6 signaling in MSC differentiation into chondrocytes.
Human bone marrow-derived MSCs were cultured using a pellet culture system in medium containing transforming growth factor β3. Chondrogenic differentiation was detected by cartilage matrix accumulation and chondrogenic marker gene expression.
IL-6 was detected at a high concentration in culture supernatants during chondrogenic differentiation. The expression of the IL-6 receptor (IL-6R) was significantly increased, accompanied by markedly increased phosphorylation and expression of STAT-3. Addition of IL-6 and soluble IL-6R (sIL-6R) to the chondrogenic culture resulted in concentration-dependent increases in cartilage matrix accumulation and cartilage marker gene expression (type II collagen/aggrecan/type X collagen). Phosphorylation of the master transcription factor SOX9 was enhanced upon addition of IL-6 and sIL-6R. STAT-3 knockdown suppressed chondrogenic differentiation. IL-6 and the MSC markers CD166 and nestin were colocalized in macroscopically normal human cartilage taken from the lateral femoral compartment of knees with medial tibiofemoral osteoarthritis.
During differentiation of human MSCs into chondrocytes, the activation of IL-6/STAT-3 signaling positively regulated chondrogenic differentiation. The presence of IL-6 around MSC-like cells in the cartilage tissue was identified, suggesting that IL-6 contributes to homeostasis and cartilage self-repair by promoting chondrogenic differentiation.”

“cartilage contains chondrogenic progenitor cells with mesenchymal stem cell (MSC)–like characteristics”<-possibly actually more like epithelial cell characteristics.

“MSCs exhibit immunosuppressive activity and inhibitory effects on osteoclast differentiation via trophic effects, by releasing various humoral factors”

“MSCs produced high levels of IL-6 during chondrogenic differentiation”

“Chondrocytes are also capable of producing IL-6 upon stimulation, although under physiologic conditions (i.e., embedded in the cartilage matrix), chondrocytes are reported to have little ability to produce IL-6”

Evaluation of the Growth Environment of a Hydrostatic Force Bioreactor for Preconditioning of Tissue-Engineered Constructs

“To determine the effect of hydrostatic pressure on bone formation, chick femur skeletal cell-seeded hydrogels were subjected to cyclic hydrostatic pressure at 0-270 kPa and 1 Hz for 1 h daily (5 days per week) over a period of 14 days. At the start of mechanical stimulation, dissolved O2 and CO2 in the medium increased and the pH of the medium decreased, but remained within human physiological ranges.”

“Hydrostatic pressure has been shown to be an important mechanical stimulus for the direction of cell fate in various tissues, including articular cartilage, the intervertebral disc, bone, and the vascular system”<-We want to induce the cell fate of chondrogenesis.

“Osteocytes in the canalicula-lacuna network of load-bearing bones are subjected to physiological pressures of approximately 270 kPa”

“he heartbeat of chick embryos delivers a dynamic pressure of 4 kPa, the blood pressure is usually between 8–24 kPa, the hydrostatic pressure in the cerebrospinal fluid is around 1.2 kPa and the interstital fluid pressure is around 0.27 kPa”

“The application of hydrostatic pressure during tissue formation could result in enhanced transfer of small molecules, such as oxygen and CO2, into the tissue matrix and provide physical forces to cells and tissues”

Biomechanics-driven chondrogenesis: from embryo to adult.

“Cartilage is relatively acellular, with chondrocytes only comprising 1–5% of the tissue by volume”

“Joint loading results in direct compression of chondrocytes inside a relatively impermeable matrix. Following tissue loading, hydrostatic pressure initially develops in the interstitial fluid, which is followed by fluid flow-induced shear. However, in time scales > 10 μs, the solid matrix begins to bear the applied load, resulting in deformation. Consequently, the cells residing in the matrix experience hydrostatic pressure, shear, compression, and, to a lesser extent, tension. This mechanical stimulation produces a signaling cascade, resulting in increased gene expression, matrix protein production, and intracellular ion influx”<-Our goal though is to induce hydrostatic pressure within the bone to induce chondrogeneic differentiation.

“Spatiotemporal changes in progenitor cell adhesion molecule expression cause similar cells to transiently associate during chondrogenesis. However, cell-cell adhesion strength correlates linearly with cellular surface tension, irrespective of a homogeneous or heterogeneous interaction, suggesting surface tension as the primary driver of differential adhesion. Therefore, precartilaginous condensation may be the result of mesenchymal progenitor cells exhibiting similar surface tensions rather than similar biomarkers. Furthermore, disruption of surface tension inhibits differential adhesion“<-so altering surface tension may be key to inducing chondrogenesis and cellular biomarkers may not necessarily be a limiting factor on chondrogenic induction.

“the absence of gravitational force reduces precartilaginous condensations in mesenchymal limb bud cells”

“Biomechanics-driven development of cartilage from embryo to fetal stages and beyond. A, B) Progenitor cells migrate from the early mesoderm to sites of skeletogenesis (A), where they undergo precartilaginous condensations (B). C) Chondrocyte progenitors secrete cartilage-specific matrix and decrease expression of cell-cell interaction proteins. D) Proliferation continues at the subchondral growth front, while endochondral ossification occurs throughout the juvenile stages to transform cartilage into bone. E) Ends of long bones remain capped with a layer of articular cartilage throughout adulthood.”

” Intermittent and cyclic hydrostatic pressure and strain both help regulate matrix protein synthesis to affect macromolecular organization of collagen fibers, which, in turn, leads to changes in the mechanical properties of the tissue ”

“models predict that intermittent hydrostatic pressure inhibits degeneration and ossification of cartilage, while intermittent strain or shear stresses accelerate ossification and degeneration”

“HP does not result in deformation of incompressible media, so it is not expected to deform cells. Direct compression results in deformation of matrix and cells, which will also create fluid flow that is not observed with HP.”

Response to mechanical loading may be differentiation dependent.

The above image is our intent where we intent to get bone marrow MSC’s to differentiate into chondrocytes.  However, we cannot isolate them in culture.

“Harnessing biomechanics to drive adult cell chondrogenesis. A) Following monolayer culture, chondrocytes rapidly dedifferentiate. Biomechanical stimuli, such as HP, can promote redifferentiation. B) Under mechanical stimulation, mesenchymal stem cells migrate and chondrodifferentiate. C) Mechanical stimulation can be used to induce transdifferentiation into chondrocytes.”

 Human mesenchymal stem cell responses to hydrostatic pressure and shear stress.

“the present study investigated the early responses of human mesenchymal stem cells (hMSCs) to intermittent shear stress (ISS) and to cyclic hydrostatic pressure (CHP) simulating some aspects of the biological milieu in which these cells exist in vivo. Production of nitric oxide (NO) and mRNA expression of several known mechanosensitive genes as well as ERK1/2 activation in the hMSC response to the two mechanical stimuli tested were monitored and compared. NO production depended on the type of the mechanical stimulus to which the hMSCs were exposed and was significantly higher after exposure to ISS than to CHP. At the conditions of NO peak release (i.e., at 0.7 Pa for ISS and 50,000 Pa for CHP), ISS was more effective than CHP in up-regulating mechanosensitive genes. ERK1/2 was activated by ISS but not by CHP. The present study is the first to report that PGTS2, IER3, EGR1, IGF1, IGFBP1, ITGB1, VEGFA and FGF2 are involved in the response of hMSCs to ISS. These findings establish that, of the two mechanical stimuli tested, ISS is more effective than CHP in triggering expression of genes from hMSCs which are bioactive and pertinent to several cell functions (such as cell differentiation and release of specific growth factors and cytokines) and also to tissue-related processes such as wound healing.”

“Exposure of the cell distal membranes to shear stress was achieved by flowing the cell-culture liquid medium through low-wall microchannels (μ-Slide) on whose surfaces (2.5 cm2) the cells were cultured; during these experiments, the medium flow was in the axial direction of the microchannels (μ-Slide).”

“PTGS2, IER3, EGR1, IGF1, IGFBP1, ITGB1, VEGFA and FGF2 genes are expressed in the response of human MSCs exposed to ISS, and that (ii) the FGF2 gene (but neither PTGES, EGR1 or VEGFA genes) are involved in the response of hMSCs to CHP. Last, but not least, the observed expression of mechano-sensitive genes (specifically, PTGS2, IER3, EGR1, IGF1, IGFBP1, ITGB1, FGF2 and VEGFA) returned to basal levels within 6 to 24 h after exposure of the hMSCs to the two mechanical stimuli tested”

Dihydrotestosterone is a determinant of calcaneal bone mineral density in men.

Full study link->DHT and IGF2

“Hundred osteoporotic men with age matched normal were studied for serum levels of sex steroids, PTH, IGF system components, cytokines and bone turnover markers. Our findings show that serum DHT, IGF-I, IGF-II and IGFBP-3 levels were significantly decreased while IL-1beta and bone turnover markers were significantly increased in osteoporotic men compared to normal. Pearson correlation analysis revealed that serum DHT, IGF-I, IGF-II and IGFBP-3 levels were positively and strongly correlated with BMD, while serum IL-1beta levels were negatively correlated with BMD. Serum PTH, testosterone, estradiol, IGFBP-4, TNF-alpha, IL-4 and IFN-gamma levels were similar between the two groups. We observed that DHT levels significantly declined with age. However, the significant difference in DHT between the osteoporotic and normal groups is the same regardless of age. A multiple regression model adjusted for age demonstrated that DHT/BMD association is fairly stronger among those with osteoporosis than the normal. Our findings for the first time point out that DHT is an important determinant of BMD in men. Most importantly, the strong positive correlation of serum DHT with BMD offers new perspectives in understanding the role of non-aromatizable androgen in regulating bone metabolism in men, and might serve as a potential clinical marker in the diagnosis of male osteoporosis.”

Serum levels of estrogen and testosterone are slightly lower in osteoperotic men than normal.

“DHT increased the levels of IGF-I and IGFBP-3 in human osteoblastic cell line (hFOB/AR-6). DHT enhances the mitogenic effect of IGF-II in bone cells.”

This is the study that mentions the link between IGF-II and DHT:
Studies of the Mechanism by which Androgens Enhance Mitogenesis and Differentiation in Bone Cells

DHT did not increase the quantity of IGF-2.

“Because FGF and IGF-II are known to synergize with TGFB, the enhanced response to FGF and IGF-II due to DHT treatment may be dependent upon the increased production of TGFB.”

DHT pre-treatment approximately doubled the effect of IGF2.

Previously, I stated that my wingspan has increased from 72.5″ to 74.5″ but I didn’t have any proof because I didn’t take any before pictures.  I’ve been trying to get my wingspan increase but haven’t had significant enough measurements for undeniable proof.  I’m keep trying to increase height and wingspan but what I can do is try to create new photos to compare to the old ones

.Here’s an image from about 2012.  I tried to recreate something like this picture as best as I could.

This was from today.  The dumbell acts as sort of a constant.

The problem is the image is not 3D so it can’t account things like the dumbell tilt.  Right now my forearm measures 11 inches elbow to wrist “bump”.  Using the dumbell handle as a constant, I compared the forearm length elbow to wrist(although it was harder to identify wrist in the before picture.  I was pretty generous to the before picture.

Before forearm length as dumbell handle lengths: 2.4 dumbell handles

After: 2.48 dumbell handles

Which is about 3%.  My wingspan increased by 2 inches.  Assume a 0.5″ of that is in my left forearm.  .5″ is about 4.76% of 10.5″.

So given the inaccuracies of the photo I don’t think it’ll be easy to have definitive proof using the two unless someone has ideas of creating a new photo standardized against the first.

Due to the significant response to my earlier post on CNP, I wanna go over all the significant studies on CNP so far.  CNP and IGF-2 seem to be the two supplement targets with the greatest potential with IGF-2 having the most potential to those without open growth plates.

BMN111 is a potential CNP analogue undergoing testing.

The bone length overgrowth effects are likely mostly due to the inhibition of FGFR3 and ERK1/2.  However, those tend to be anabolic in other tissues so CNP will most likely make you taller and lankier.

Meclizine is a supplement that is similar to some effects of CNP, inhibition of ERK1/2 but is available for sale.  This post has some other information about meclizine as well as why FGFR3 inhibition is effective for height growth.

Meclizine Chewable Tablets – 25mg – Model 85207 – (3 Bottles of 100)

Note: Disobey any directions on the bottle at your own risk. I don’t know the optimal dosage. Also, this should only be offective on open plates.

Inflammation in children reduced CNP production so inhibiting inflammation should increase CNP levels.

As for possible ways CNP could increase height in those with closed growth plates:

Increased bone turnover and possible accelerated fracture healing in a murine model with an increased circulating C-type natriuretic peptide.

” we investigated the bone phenotype of a mouse model with elevated plasma CNP concentrations (SAP-CNP-Tg mice) in the present study. Micro-CT analysis revealed less bone in femurs, but not in lumber vertebrae, of young adult SAP-CNP-Tg mice than that of wild-type mice{CNP could weaken bone allowing for neo-growth plate formation}. Bone histomorphometry of the tibiae from 8-week-old SAP-CNP-Tg mice showed enhanced osteoblastic and osteoclastic activities, in accordance with elevated serum levels of osteocalcin and TRAP5b, respectively. Next we performed an open and stabilized femoral fracture using 8-week-old SAP-CNP-Tg mice and compared the healing process with age-matched wild-type mice. Immunohistochemical study revealed that CNP and its receptors, natriuretic peptide receptor-B (NPR-B) and natriuretic peptide clearance receptor are expressed in hard calluses of wild-type mice, suggesting possible role of CNP/NPR-B signaling in fracture repair, especially in bone remodeling stage. On micro-CT analysis, rapid decrease in callus volume was observed in SAP-CNP-Tg mice, followed by generation of significantly higher new bone volume with a tendency of increased bone strength. In addition, micro-CT analysis also showed that bone remodeling was accelerated in SAP-CNP-Tg mice, which was also evident from increased serum osteocalcin and TRAP5b levels in SAP-CNP-Tg mice at remodeling stage of fracture repair. These results indicate that CNP activates bone turnover and remodeling in vivo and possibly accelerates fracture healing in our mouse model.”

CNP overexpression also decreased bone stiffness.