Grow in Stature with Osteons

You are capable of growing taller by bone deposition beneath the periosteum, some bones however are not completely covered by periosteum.  Some bones grow in apposition due to a spherical growth plate(which does not help us unless the histology shows us that some of the cartilage of the plate is maintained).

There are other ways to specifically grow taller and one is directly by the haversian system within the osteon.  How can we get bone growth at the longitidunal ends of the bones when there is no periosteum due to articular cartilage coverage?  There is bone on the surface of the ends of the epiphysis of the long bones.  Therefore it is capable of growing in length at that position do to direct bone deposition within the osteon.

Also, humans with lowered SOST have empirical evidence of increased height.

Interstitial fluid flow in the osteon with spatial gradients of mechanical properties: a finite element study.

"Bone [are] a porous deformable{LSJL causes bone deformation} material whose pores are filled with cells, organic material and interstitial fluid. Fluid flow [plays] a role in the mechanotransduction of signals for bone remodelling{LSJL increases fluid flow}. An osteon, the elementary unit of cortical bone, is a hollow cylinder made of a deformable porous matrix saturated with an interstitial fluid. Results on fluid flow in osteons: (i) a permeability gradient affects more the fluid pressure than the velocity profile; (ii) focusing on the fluid flow, the key element of loading is the strain rate; (iii) a Poisson's ratio gradient affects both fluid pressure and fluid velocity."

"The typical loading frequency is chosen to be 1 Hz which corresponds to walking activity. Results for interstitial fluid pressure and fluid velocity in the radial direction of the osteon are exhibited at half the height of the osteon, i.e. at z = h/2, when the pressure peak is reached, i.e. when the maximal compression effect is observed."

"Pressure builds up toward the outside radius"

"The fluid flows from the Haversian canal to the cement line and is thus strongly dependent on the inflow-outflow conditions"

"Interstitial fluid flow leads to higher pressure values when permeability decreases toward the outside radius"<-the more dense the bone the lower the permeability will be since LSJL increases bone density bone permeability will decrease over time and result in higher pressure over time.

"Solid matrix deformation drives fluid flow because the imposed mechanical loading is introduced through the longitudinal deformation of the porous matrix."

Osteocyte and bone structure

"The osteocyte is the most abundant cell type of bone. There are approximately 10 times as many osteocytes as osteoblasts in adult human bone, and the number of osteoclasts is only a fraction of the number of osteoblasts. osteocytes [are] professional mechanosensory cells of bone, and the lacunocanalicular porosity [is] the structure that mediates mechanosensing. Strain-derived flow of interstitial fluid through this porosity seems to mechanically activate the osteocytes, as well as ensure transport of cell signaling molecules, nutrients, and waste products. Local bone gain and loss--as well as remodeling in response to fatigue damage--[are] processes supervised by mechanosensitive osteocytes. Alignment during remodeling [occurs] as a result of the osteocyte's sensing different canalicular flow patterns around the cutting cone and reversal zone during loading, therefore determining the bone's structure."

Osteocytes are found in cortical bone and not necessarily just beneath the periosteum.  Osteocytes can deposit new bone.  New bone deposition on the longitudinal surfaces of the bone may result in height gain.  Osteocytes are trapped in the bony matrix but may be released as a result of microfractures(which may possibly be caused by LSJL).  Unfortunately, there are no haversian systems in the epiphysis of bones.  Note however that if you look at the histology of epiphyseal bone under LSJL, you can see bone increasing in thickness and width.  Possibly, indicating the formation of new osteons in the epiphysis of the bone.

Structure, formation and role of cartilage canals in the developing bone.

"Endochondral bone development depends upon neovascularization, and the early generation of vascularized cartilage canals is an initial event, preceding the formation of the SOC. These canals form a discrete network within the cartilaginous epiphysis giving rise to the formation of the marrow space followed by the establishment of the SOC. These processes require excavation of the provisional cartilaginous matrix which is eventually replaced by permanent bone matrix. Attention is paid to the enzymes required in disintegration of the cartilaginous matrix which, in turn, will allow for the invasion of new vessels. Mesenchymal cells of the cartilage canals express bone-relevant proteins and transform into osteocytes. the canals are essential for normal epiphyseal bone development, the establishment of the growth plate and ultimately longitudinal growth of the bones."

If you block the enzymes responsible in the disintegration of the cartilaginous matrix, the epiphysis will never fuse with the diaphysis.

The creation of new Haversian systems and deposition of new bone on the ends by osteocyte signaling is another possible mechanism of LSJL along with the fibrous capsule.

"The canals begin as invaginations of the perichondrium and invade the non-calcified epiphyseal cartilage matrix. They bear blood vessels, loose connective tissue (=undifferentiated mesenchymal stem cells embedded within an extracellular matrix) and multivacuolated cells terminating blindly in capillaries forming glomerulus-like structures. These capillaries recombine into a single venule rejoining the perichondrium via the same canal. Vessels and cells are embedded in an electron translucent matrix and no continuous epithelium is elaborated at the canal border. [Cartilage canals] constitute a network well before the establishment of the SOC."

"The ingrowth and advancement of the vessels first requires a battery of cells capable of disintegrating the most abundant components of the cartilaginous matrix such as fibrillar type II collagen and the main proteoglycan, aggrecan[likely MMPS(MMP-9, MMP-13, and MT-1MMP, also TRAP; MT-1MMP being essential but MMP's 9 and 13 much less so with only minor delays if both are absent individually but major issues if both are absent].  [The study mentions that endochondral ossification can occur without the formation of cartilage canals but cartilage canals are a source of MSCs and nutrients] Secondly, cells are needed to reabsorb the remnants of the degraded extracellular matrix. Thirdly, angiogenic factors are required to stimulate vessel growth. These cells and factors interact in a temporally well-coordinated manner, creating a suitable environment and clearing a path for the invasion of vessels as well as mesenchymal cells."

Here's a study that explains how osteocytes regulate existing mRNA in the bone.  So it answers the question how much does the development of bone inhibit chondrogenesis:

Hydroxyapatite Modulates mRNA Expression Profiles in Cultured Osteocytes

"Osteocytes in vivo present a unique pattern of gene expression necessary for bone remodeling and mineral metabolism. Genes expressed in osteocytes such as Sost and fibroblast growth factor 23 (FGF23) are essential for load-driven bone formation and regulation of phosphate in the serum, respectively[FGF23 is involved in chondrocyte differentiation so it's a good thing]. However, their expression levels in standard cell cultures are significantly low and the mechanism of their transcriptional regulation is hardly examined. Since osteocytes reside in hydroxyapatite (HA)-surrounded lacunae, in this in vitro study we addressed a question whether they would exhibit mRNA expression profiles close to in vivo in the presence of HA. HA [provides] a three-dimensional (3D) growth environment important for the regulation of many of the osteocyte characteristic genes. To test this hypothesis, we grew MLO-A5 cells in a 3D collagen matrix with and without HA deposition and conducted a genome-wide expression analysis. deposition of HA markedly elevated the mRNA levels of Sost, dentin matrix protein 1 (DMP1), and FGF23. The microarray derived data indicated potential involvements of Wnt and PI3K signaling. Protein and mRNA expression analysis using pharmacological inhibitors such as LY294002 and pertussis toxin showed that HA-driven gene regulation was in part mediated by Akt in a PI3K pathway and G-protein linked receptors. HA [provides] a growth environment that enabled osteocytes to stimulate their characteristic genes such as Sost, DMP1, and FGF23."

The study states that the increase in FGF23 could be mediated via GPR's so that's something to look at.

"In response to mechanical stimulation, osteocytes reduce the production of Sost, which is an inhibitory ligand of a Wnt receptor complex including a low-density-lipoprotein receptor-related protein 5 (Lrp5)."

"the HA-rich environment induces PI3K signaling and enhances the expression of Connexin 43. Connexin 43 is a gap junction protein, which plays a critical role for cell-to-cell interactions by linking one osteocyte to another and to the bone surface. It is reported in cultured osteocytes that prostaglandin driven upregulation of Connexin 43 is suppressed by the PI3K inhibitor."

Here's a study by CH Turner with more on SOST:

High-bone-mass-producing mutations in the Wnt signaling pathway result in distinct skeletal phenotypes.

"Dkk1 and sclerostin bind to different β-propeller domains of the Lrp5 receptor, and their inhibitory action is additive, not synergistic.  Dkk1 is a much stronger binding partner to WT Lrp5 than is sclerostin, and it is able to displace pre-bound sclerostin from the receptor. In the Lrp5 mutants we studied, Dkk1 would presumably have had no effect on Lrp5 signaling, whereas in the Sost mutants, Dkk1 should be fully capable of inhibiting Wnt/Lrp5 signaling. The observation that Sost mutants have such high bone mass suggests little compensation by the other Wnt signaling inhibitors, including Dkk1, to keep bone formation in check in the absence of sclerostin. Conversely, removal of sclerostin from the system (e.g., Sost mutants) would not “free up” any new binding sites for Dkk1 since this molecule does not compete for the same binding site on Lrp5, nor does it interact with sclerostin. Recently, it was reported that sclerostin requires a co-factor, identified as Lrp4, to exert its inhibitory effect on Lrp5/6 action in bone cells"<-LSJL alters Dkk expression.

Sost KO mice had increased bone mass but no effect on length was mentioned.

This study states that Sost inhibition and in turn possibly Dkk1 inhibition may have a height increasing effect.

Sclerostin antibody treatment enhances bone strength but does not prevent growth retardation in young mice treated with dexamethasone.

"Exposure to supraphysiologic levels of glucocorticoid drugs is known to have detrimental effects on bone formation and linear growth. Patients with sclerosteosis lack the bone regulatory protein sclerostin, have excessive bone formation, and are typically above average in height. This study was undertaken to characterize the effects of a monoclonal antibody to sclerostin (Scl-AbI) in mice exposed to dexamethasone (DEX).
Young mice were concomitantly treated with DEX (or vehicle control) and Scl-AbI antibody (or isotype-matched control antibody [Ctrl-Ab]) in 2 independent studies. Linear growth, the volume and strength of the bones, and the levels of bone turnover markers were analyzed.
In DEX-treated mice, Scl-AbI had no significant effect on linear growth when compared to control treatment (Ctrl-Ab). However, in mice treated with DEX and Scl-ABI, a significant increase in trabecular bone at the femoral metaphysis (bone volume/total volume +117% versus Ctrl-Ab-treated mice) and in the width and volume of the cortical bone at the femoral diaphysis (+24% and +20%, respectively, versus Ctrl-Ab-treated mice) was noted. Scl-AbI treatment also improved mechanical strength (as assessed by 4-point bending studies) at the femoral diaphysis in DEX-treated mice (maximum load +60% and ultimate strength +47% in Scl-AbI-treated mice versus Ctrl-Ab-treated mice). Elevated osteocalcin levels were not detected in DEX-treated mice that received Scl-AbI, although levels of type 5b tartrate-resistant acid phosphatase were significantly lower than those observed in mice receiving DEX and Ctrl-Ab.
Scl-AbI treatment does not prevent the detrimental effects of DEX on linear growth, but the antibody does increase both cortical and trabecular bone and improves bone mechanical properties in DEX-treated mice."

So maybe the increase in height in Sost minus patients in a coincidence or maybe the thicker bones increase height in a mechanism not related to endochondral ossification.

"Although the growth plate itself did not contain sclerostin-positive cells, there were nests of cells adjacent to the growth plate that were positive for sclerostin expression"

"down-regulation of Dkk-1 (a Wnt antagonist) with antisense oligonucleotides protected bone from the effects of GC exposure."

"the large stature of individuals with a defective sclerostin gene"

Sost inhibition may be a novel non-growth plate way of increasing height.

Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin.

"Sclerostin, the protein product of the Sost gene, is a potent inhibitor of bone formation. Among bone cells, sclerostin is found nearly exclusively in the osteocytes, the cell type that historically has been implicated in sensing and initiating mechanical signaling. The recent discovery of the antagonistic effects of sclerostin on Lrp5 receptor signaling, a crucial mediator of skeletal mechanotransduction, provides a potential mechanism for the osteocytes to control mechanotransduction, by adjusting their sclerostin (Wnt inhibitory) signal output to modulate Wnt signaling in the effector cell population. We investigated the mechanoregulation of Sost and sclerostin under enhanced (ulnar loading) and reduced (hindlimb unloading) loading conditions. Sost transcripts and sclerostin protein levels were dramatically reduced by ulnar loading. Portions of the ulnar cortex receiving a greater strain stimulus were associated with a greater reduction in Sost staining intensity and sclerostin-positive osteocytes (revealed via in situ hybridization and immunohistochemistry, respectively) than were lower strain portions of the tissue. Hindlimb unloading yielded a significant increase in Sost expression in the tibia. Modulation of sclerostin levels appears to be a finely tuned mechanism by which osteocytes coordinate regional and local osteogenesis in response to increased mechanical stimulation, perhaps via releasing the local inhibition of Wnt/Lrp5 signaling."

"Sections from the proximal portion of the ulnar diaphysis, which experiences relatively small peak strains during ulnar loading, exhibited a modest (∼15%) reduction in Sclr+ cells, whereas sections from the distal diaphysis, which experiences relatively large peak strains during loading, showed a ∼60% reduction in Sclr+ cells"

"Dkk1 transcripts were also reduced significantly by loading, albeit to a lesser degree than Sost, reaching a 49% decrease induced by loading"

SOST transcripts have been detected in bone marrow.

BONE OVERGROWTH-ASSOCIATED MUTATIONS IN LRP4 IMPAIR SCLEROSTIN-FACILITATOR FUNCTION

"the interaction of sclerostin with LRP4 is required to mediate sclerostin’s inhibitory function on bone formation"

"LRP4 mutations are associated with bone overgrowth and impaired sclerostin-facilitator function."

"Sclerostin-mediated inhibition of Wnt1/β-catenin signaling is enhanced by LRP4" In a chondrocyte cell line overexpression of LRP4 resulted in an increase in Beta-Catenin inhibition.

In the study a mention of a male with tale stature with SOST is made.  This patient had a mutation in LRP4.

Given that reducing SOST results in increased height but that this height does not seem to result in the growth plate.  SOST may play a new novel method of height growth.  Since loading increasing decreases SOST, it would be easy to use anecdotal evidence to verify load based increase on height.

Although this study suggests that LRP4 knockout may result in undergrowth so you may need a specific mutation to grow taller as a result of LRP4.

Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice.

"Homozygous Megf7[LRP4]-deficient mice are growth-retarded"

Do people who use extreme loads gain height?  There are confounding variables like the intervertebral discs. However, you could just measure the long bone directly or look at wingspan or arm length.  Do heavy benchers get longer arms?

Osteocyte Signaling in Bone

"Osteocytes [are] the cells residing within the bone matrix and comprising 90 % to 95 % of the all bone cells.  Osteocytes are the principal sensors for mechanical loading of bone. They produce the soluble factors that regulate the onset of both bone formation and resorption. Osteocytes regulate local mineral deposition and chemistry at the bone matrix level, and they also function as endocrine cells producing factors that target distant organs such as the kidney to regulate phosphate transport."

Thus osteocytes may regulate growth plate development or possibly trigger signaling for new growth plate formation.

"[Osteocytes are] derived from the osteoblast lineage and is morphologically characterized by distinct dendritic processes that emanate from the cell body and connect with other osteocytes, cells at the bone surface, and nearby blood vessels. The cell body is located in an ellipsoidal space called a lacuna, while the dendritic processes reside in tiny cylindrical channels called canaliculi (~250–300 nm in diameter)"

"The transformation from plump collagen-producing osteoblasts to smaller dendritic osteocytes is a dramatic one that requires extensive restructuring of the cytoskeletal and intracellular machinery. For example, having undergone the transition osteocytes typically have lost the apical and basolateral plasma membrane polarization normally seen in osteoblasts "

"constitutive molecular markers for osteocytes [include] low collagen and alkaline phosphatase production, high casein kinase II and osteocalcin protein expression, high CD44, dentin matrix protein 1 (DMP1), phosphate-regulating neutral endopeptidase on chromosome X (PHEX), matrix extracellular phosphoglycoprotein (MEPE), sclerostin, fibroblast growth factor 23 (FGF-23), osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL)."

"apoptosis is necessary to initiate intracortical bone remodeling following fatigue-induced microdamage."<-inhibition of apoptosis blocked resorption by osteoclasts.