Relating Osteoarthritis to height increase

Osteoarthritis involves endochondral ossification of the articular cartilage tissue.  Since endochondral ossification should have an hypertrophic phase for chondrocytes this should result in an increase in height(not that I am recommending it but studying it might provide some insight into potential height increase endeavors).  For endochondral ossification to occur in cartilage,  there must not be an Extra cellular Matrix which is regulated by Sox9.  Increasing Sox9 has been proposed to inhibit the late stages of enchondral ossification possibly allowing you to keep the hyaline cartilage growth plate line there for longer and get more stem cells there via LSJL or other means.  What other insights can we acquire from analyzing osteoarthritis?

Is osteoarthritis a disease involving only cartilage or other articular tissues?

"Osteoarthritis results from a complex system of interacting mechanical, biological, biochemical, molecular and enzymatic feedback loops. The final common pathway is joint tissue destruction resulting from the failure of cells to maintain a homeostatic balance between matrix synthesis and degradation[ECM]. As the disease advances, the degradative process eventually exceeds the anabolic process, leading to progressive joint tissue lesions. This appears to occur when the physiological balance between the synthesis and degradation of the extracellular matrix favours catabolism."

The ECM and Sox9 are what seem to block endochondral ossification in the articular cartilage.

"Osteoarthritis of the knee is a heterogeneous chronic disease involving the entire organ, including the articular cartilage, subchondral bone, menisci, and periarticular soft tissues such as synovial membrane. In this disease, the occurrence of alterations in cartilage metabolism is well established, and data suggest that the changes are primarily the result of a disturbance in the remodelling process of this tissue. Moreover, in this disease, the participation and role of synovial inflammation are now widely accepted[histamine]. Synovitis appears to result from the synthesis and release of many factors and is considered to be secondary to the changes in the cartilage. Yet, findings indicate that synovial inflammation could be a component of the early events leading to the clinical stage of OA. In addition, emerging evidence suggests that changes in subchondral bone[subchondral bone is the epiphysis] and menisci are closely involved in the disease progression. Data even suggest that the subchondral bone alterations may precede cartilage changes. In brief, subchondral bone is suggested to be the site of the causally most significant pathophysiological events occurring in cartilage."

"The cartilage matrix consists of macromolecules of which collagen and proteoglycans (aggrecans) are the main representatives[anything that increases aggrecan content will increase height such as dynamic loading of chondrocytes]. These components are highly ordered from the cartilage surface to the deepest layers. Cartilage is divided into four zones with different functions: the superficial, middle or transitional, deep or radial, and calcified cartilage zones[this seems a lot like endochondral ossification], without a sharp boundary between the first three zones."

"In OA cartilage, chondrocytes synthesize proteases that cleave the proteoglycan monomer releasing fragments which rapidly diffuse from cartilage into the synovial fluid, leaving behind normal proteoglycan still capable of aggregation. New aggrecan synthesis does occur in OA cartilage, presumably in an attempt by the chondrocytes to initiate repair. The newly synthesized aggrecan forms proteoglycan aggregates that are retained in the cartilage during the early stages of OA, but in later stages they are also lost to the synovial fluid. The newly synthesized aggrecan has a composition more similar to juvenile cartilage than adult cartilage. At a certain stage in the evolution of OA, the chondrocytes appear unable to compensate fully for proteoglycan loss even in the presence of its increased synthesis, resulting in a net loss of matrix. The rate at which proteoglycan synthesis and degradation occur may vary in different regions of the cartilage, due to differences in the mechanical stress to which it is subjected."

"one response of the OA knee to increased load is for the tibial plateau to expand" which would increase height.  If the tibial plateau is capable of expanding then height can be increased.  The tibial plateau is the top of the tibia.

"inducible NO acts by reducing the major anabolic processes and increasing the catabolic processes, making it a complete factor favoring joint destruction."

Supplementing with Nitric Oxide may or may not be recommended.  The jury is still out.

You can read the full study here.  That research on osteoarthritis has implications on height increase and LSJL is clear.  Osteoarthritis involves interactions between the epiphysis and the articular cartilage which is the same as LSJL.  Osteoarthritis involves both anabolic and catabolic processes.  As long as you keep proteoglycan synthesis high you should not develop osteoarthritis.  Since dynamic loading of chondrocytes induces aggregan synthesis which LSJL involves chondrocyte loading, the changes in the epiphysis and the cartilage itself should balance out.

Here's a study involving osteoarthritis that shows that bone cells can induce chondrogenic differentiation:

Crosstalk between cartilage and bone: when bone cytokines matter.

"The cartilage damage which characterizes osteoarthritis is often accompanied by bone lesions. Joint integrity results from the balance in the physiological interactions between bone and cartilage. Several local factors regulate the physiological remodeling of cartilage, the disequilibrium of these leading to a higher cartilage catabolism. Several cytokines secreted by bone cells can induce chondrocyte differentiation[so get these cytokines to be secreted by bone cells to induce height growth], which suggests their role in the dialogue between both cells. Accumulative in vivo evidence shows that increased bone resorption occurs at an early stage in the development of osteoarthritis and that blocking bone-resorbing cytokines prevents cartilage damage, confirming the role of bone factors in the crosstalk of both tissues. Recently, molecules of the Wnt pathway have emerged as key regulators of bone and cartilage[LSJL has been shown to upregulate genes in the Wnt signaling pathway]. Activation of Wnt/βcatenin induces an imbalance in cartilage homeostasis, and agonists/antagonists of Wnt are potential candidates for this interaction. This review will summarize what is known about the contribution of bone cytokines to the physiological remodeling of cartilage and in the pathophysiology of osteoarthritis."

"The distribution and damping of mechanical loading depends on the quality of the subchondral bone and the mechanical competence of cartilage is probably influenced by the mechanical properties of the bone plate beneath the cartilage and the trabecular network. As cartilage remodeling is influenced both by bone quality and by the magnitude of mechanical loading, the mechanical strains exerted on subchondral and trabecular bone are different. Mechanical strains in the deep cartilage layer are greater in subchondral plates with high density, as they can also exist on high-density trabecular bone. Structure, bone mineral density and cellular activity all differ in subchondral and trabecular bone, and confer their specific mechanical properties. The apparent bone density (bone mass/total mass) measured beneath the cartilage of patients with OA is higher than in those without OA, although their bone mineral density is reduced"<-So the density of the trabecular and subchondral bone affects the loading of the cartilage.

"In guinea pigs that develop spontaneous knee OA, bone volume increases in parallel to cartilage wear"

According to the Study, "Moderate Joint Loading Reduces Degenerative Actions of Matrix Metalloproteinases in the Articular Cartilage of Mouse Ulnae" joint loading reduced the effects of MMP-1, 3, and 13 in contrast with this osteoarthritis information that states that cartilage damage from osteoarthritis increases MMP-1, 3, and 13.  So it's unlikely that LSJL mimics the early stages of osteoarthritis.

"the bone changes observed in OA are related to osteoblast dysfunction. Indeed, osteoblasts derived from OA patients proliferate more and express more alkaline phosphatase and collagen type I than controls"

"IGF-1 and plasminogen activators that mediate the effect of IGF-1 may be involved, since osteoblasts from OA patients produce more IGF-1 than control osteoblasts"

"TGF-β is highly expressed in OA bone, whereas OA chondrocytes have a low TGF-β response. TGF-β favors the recruitment of osteoblast precursors and activates the production of type I collagen while reducing the hypertrophic maturation of chondrocytes"

"intermittent injection of exogenous PTH leads to a bone gain related to increased bone turnover. Both osteoclast and osteoblast activities are enhanced; the anabolic effect is higher than the catabolic effect, although the exact mechanism is unknown. Deletion of the PTHgene in mice revealed reduced trabecular bone related to a decreased osteoblast number and enhanced osteoblast apoptosis. PTH stimulates the production of IL6 by osteoblasts[thus perhaps you can simulate the benefits of PTH by increasing IL6 production?], which in turn stimulate the production of RANKL and OPG. The anabolic action of PTH might be also mediated by the canonical Wnt signaling pathway. Increased resistance to PTH has been reported in OA bone, which might explain the increase in bone formation. Moreover, IGF-1 downregulates the expression of PTH receptors, resulting in an increased resistance to PTH by OA osteoblasts. Aside from the action of PTH in osteoarthritic osteoblasts, PTH exerts a direct effect on chondrocytes. PTH diminishes the differentiation of articular chondrocytes in vitro[so PTH may let the growth plates stay "open" longer] and indeed protects against OA when injected locally in rats"

"Osteoblasts derived from patients with OA downregulate chondrocyte-specific genes (Sox9, Coll2 and PTH-R), suggesting that local factors may initiate chondrocyte hypertrophy"<-so to grow taller you'd want to enhance the osteoblast expression of Sox9, Coll2, and PTH-R

"Cathepsin K, a cystein protease mainly expressed by osteoclasts, is involved in osteoclastic function and bone resorption via the cleavage of type I collagen. Cathepsin K is also expressed in OA articular chondrocytes and is able to cleave type II collagen. Hence, partial deletion of type II collagen in Del1 mice increases its expression in chondrocytes. Indeed, cathepsin K transgenic mice are known to develop cartilage degradation with age. We can therefore hypothesize that the inhibition of cathepsin K could prevent cartilage and bone loss"<-Inhibition of Cathepsin K by osteoclasts may help normal individuals grow taller as well.

Here's a study involving Osteoarthritis that may have valuable insights on height growth pathways:

Insights on Biology and Pathology of HIF-1alpha/-2alpha, TGF-Beta/BMP, Wnt/Beta-Catenin, and
NF-kappaB Pathways in Osteoarthritis

"HIF-1α promotes chondrocyte differentiation and survival, while HIF-2α coactivates with β-catenin and NF-κB pathways to promote chondrocyte apoptosis and endochondral ossification[Thus we need HIF-1alpha to induce chondrogenesis and HIF-2alpha to induce endochondral ossification]. Depending on the ALK1/ALK5 ratio in chondrocytes, the TGFβ pathway can play an anabolic or catabolic role[We need to manipulate the ALK1/ALK5 ratio so that TGFBeta plays an anabolic role]. TGFβ1 can activate the β-catenin signaling pathway via ALK5, Smad3, PI3K, and PKA pathways. The mediator Axins balance TGF-β and Wnt/β-catenin signaling during chondrocyte proliferation and maturation. However, the biological functions of Wnt/β-catenin signaling are still controversial. Both excessive and insufficient β-catenin levels may impair the homeostasis of articular chondrocytes by enhancing pathological maturation and apoptosis, respectively; loss- and gain-of-functions of β-catenin cause apoptosis at the center of the joint and chondrocyte maturation at the periphery, depending on the vascularity[Thus it would be difficult to manipulate Beta-catenin levels to grow taller]. The NF-κB transcription factor can be triggered by a host of stress-related stimuli including pro-inflammatory cytokines. The recent discovery of functional cross-regulation between these pathways has shown complex roles for HIF-1α/HIF-2α, TGFβ/BMP, Wnt/β-catenin, and NF-κB signaling pathways in the pathogenesis of OA. This has important implications for potential therapeutic agents directed at these pathways. This review attempts to cover the literature of the past three years dealing with the biology and pathology of the HIF-1α/-2α, TGFβ/BMP, Wnt/β-catenin, and NF-κB/cytokines signaling pathways in OA."

"In contrast to HIF-1alpha acting as a survival factor in chondrocytes, HIF-2alpha does not seem to control ECM synthesis and apoptosis of chondrocytes, but acts as a catabolic factor in cartilage destruction by regulating expression of target genes in chondrocytes."

"HIF-1alpha was found to not only induce the expression of SOX9, COL2A1, and aggrecan {all three are upregulated by LSJL}, but simultaneously to inhibit the expression of COL1A1{upregulated by LSJL}, COL1A2, and COL3A1{upregulated by LSJL}, which indicates the bifunctional role of HIF-1alpha in differentiation and dedifferentiation"<-So HIF-1alpha encourages cartilage growth and discourages bone growth.

"HIF-1alpha negatively regulates Wnt/Beta-catenin signaling by directly sequestering Beta-catenin from Beta-catenin/TCF. However, HIF-2alpha binds to Beta-catenin and enhances the transcriptional activity of Beta-catenin/TCF by recruiting p300."

"Autophagy is an intermediate step in the chondrocyte life cycle that permits the cells to assume a mature phenotype, prior to elimination by apoptosis"

"Smad6 preferentially down-regulates BMP signaling, while Smad7 down-regulates TGF-Beta, activin, and BMP pathways. Smurfs show Smad specificity (and therefore pathway specificity), with Smurf1 targeting Smad 1 and 5, and Smurf2 targeting Smad 2 and 3."

"the interaction of Smad3 with Runx2 inhibits Runx2 function"<-So TGF-Beta inhibits Runx2 function.

"In aged and OA articular chondrocytes, ALK5 expression decreases much more than ALK1. Thus, the ALK1/ALK5 ratio increases"<-This may be why people stop growing taller if ALK5 expression decreases in stem cells.

"In human OA cartilage, ALK1 is highly correlated with MMP-13 expression, whereas ALK5 correlates with aggrecan and collagen type II expression."<-If ALK1/ALK5 are expressed in stem cells this could change in balance could disrupt chondrogenic differentiation.

"TGF-Beta1 activates the Beta-catenin signaling pathway via ALK5, Smad3 PI3K and PKA pathways (the last two in a non-Smad dependent manner) in hMSCs"<-So ALK5 is expressed in MSCs

"enhancement of chondrogenesis by BMP-2 is mediated via a SOX9-dependent pathway. However, BMP activity not only elevated SOX9 expression, but also stimulated the chondrogenic capacity of SOX9 by forming a SOX9-CREB complex and promoting DNA binding"

"Wnt/Beta-catenin induces cell senescence and MMP expression; it simultaneously promotes the expression of aggrecan through the anabolic factor TGF-Beta3, which indicates that Wnt/Beta-catenin signals regulate the balance between catabolic factors and anabolic factors"

Here's a study by Hiroki Yokota involving EIF2alpha, MMP-13, and MAPK which may all play roles in height increase:

Involvement of p38 MAPK in regulation of MMP13 mRNA in chondrocytes in response to surviving stress to endoplasmic reticulum.

"Using C28/I2 chondrocyte cell line, ER stress was induced by thapsigargin and tunicamycin and upregulation of phosphorylated eIF2alpha and ATF4 protein was observed. Both thapsigargin and tunicamycin elevated the mRNA level of MMP13 and phosphorylation of p38 MAPK. Thapsigargin-induced MMP13 mRNA upregulation was significantly suppressed by SB203580, while its upregulation by tunicamycin was completely attenuated by SB203580[an MAPK p38 inhibitor]. Those results support that homeostasis of chondrocytes is affected by the surviving ER stress through p38 MAPK pathways, suggesting a potential role of ER stress in joint diseases such as osteoarthritis."

"Thapsigargin is an inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase[Since Ca2+ secretions are involved in chondrogenic differentiation thapisargin may affect height either positively or negatively], and tunicamycin is an inhibitor of N-linked glycosylation and the formation of N-glycosidic protein-carbohydrate linkages"

"A significant increase of > 2-fold was observed in expression of ATF3 (1 – 5 h), CHOP (3 – 10 h), and MMP13 (1 – 10 h), where T3h gave a higher mRNA level than T1h. The mRNA levels of ATF4 (3 and 5 h), GADD45β (3, and 5 h), and MMP1 (5, and 10 h) were significantly elevated, although the increases were ~ 50% or less."<-this is in response to thapisargin.  So no pro-chondrogenic genes in response to thapisargin, thus thapisargin likely has no or a negative effect on chondrogenesis.

Further evidence of thapisargin not enhancing chondrogenesis: "The mRNA levels of Col2A1, Col10A1, and aggrecan were mostly unchanged except for slight elevation for T1h at 10 h."  "Expression of Sox9 mRNA and Runx2 mRNA was unchanged or decreased by thapsigargin-induced surviving ER stress."  Thapisargin may have a different response on stem cells than chondrocytes however.


Combination of MEK-ERK inhibitor and hyaluronic acid has a synergistic effect on anti-hypertrophic and pro-chondrogenic activities in osteoarthritis treatment.

"Chondrocyte differentiation and hypertrophy were evaluated using human OA primary cells treated with either HA[Hyaluronic Acid] or U0126[an MEK-ERK inhibitor], or the combination of HA + U0126. Cartilage degeneration in menisectomy (MSX) induced rat OA model was investigated by intra-articular delivery of either HA or U0126, or the combination of HA + U0126. Phosphorylated ERK (pERK)1/2-positive chondrocytes were significantly higher in OA samples compared with those in healthy control suggesting the pathological role of that pathway in OA. It was noted that HA + U0126 significantly reduced the levels of pERK, chondrocyte hypertrophic markers (COL10 and RUNX2) and degenerative markers (ADAMTs5 and MMP-13), however, increased the levels of chondrogenic markers (COL2) compared to untreated or the application of HA or U0126 alone. In agreement with the results in vitro, intra-articular delivery of HA + U0126 showed significant therapeutic improvement of cartilage in rat MSX OA model compared with untreated or the application of HA or U0126 alone."