CTGF(CCN2), height increase target gene

 CCN2 could increase adult height by accelerating the rate of endochondral ossification but keeping the epiphyseal growth plate the same size resulting in more growth.  CCN2 is also associated with the height gene IGF2.

CTGF meets the criteria for a height growth target where overexpression increases height and underexpression decreases height.  However this was only for cartilage specific expression of CTGF.  Overexpression of CTGF has been found to have catabolic effects on muscle.

Glucosamine and CLA are potential ways to increase CTGF levels however can a global increase of CTGF increase height like a cartilage specific one?  Does anyone know any other supplements that can increase CTGF?  Prefereably only in the cartilage. 

It should be noted that CTGF is only a promising target for people with open growth plates.

Cartilage–Specific Over-Expression of CCN Family Member 2/Connective Tissue Growth Factor (CCN2/CTGF) Stimulates Insulin-Like Growth Factor Expression and Bone Growth

"CCN family member 2/connective tissue growth factor (CCN2) promotes the proliferation, differentiation, and maturation of growth cartilage cells in vitro.  We generated transgenic mice overexpressing CCN2 and analyzed them with respect to cartilage and bone development. Transgenic mice were generated expressing a ccn2/lacZ fusion gene in cartilage under the control of the 6 kb-Col2a1-enhancer/promoter. Changes in cartilage and bone development were analyzed. Primary chondrocytes as well as limb bud mesenchymal cells were cultured and analyzed for changes in expression of cartilage–related genes, and non-transgenic chondrocytes were treated in culture with recombinant CCN2. Newborn transgenic mice showed extended length of their long bones, increased content of proteoglycans and collagen II accumulation. Transgenic bones indicated increases in bone thickness and mineral density. Chondrocyte proliferation was enhanced in the transgenic cartilage. In in vitro short-term cultures of transgenic chondrocytes, the expression of col2a1, aggrecan and ccn2 genes was substantially enhanced; and in long-term cultures the expression levels of these genes were further enhanced. Also, in vitro chondrogenesis was strongly enhanced. IGF-I and IGF-II mRNA levels were elevated in transgenic chondrocytes, and treatment of non-transgenic chondrocytes with recombinant CCN2 stimulated the expression of these mRNA. The addition of CCN2 to non-transgenic chondrocytes induced the phosphorylation of IGFR, and ccn2-overexpressing chondrocytes showed enhanced phosphorylation of IGFR. The observed effects of CCN2 may be mediated in part by CCN2-induced overexpression of IGF-I and IGF-II. CCN2-overexpression in transgenic mice accelerated the endochondral ossification processes, resulting in increased length of their long bones."

" At 8 weeks, the majority of the transgenic mice were about 12% larger than their wild-type littermates"

"Safranin-O staining indicated consistently an enhanced density of proteoglycans in the transgenic cartilage in comparison with cartilage of wt littermates"

"type II collagen [had] an enhanced reaction in resting chondrocytes and in the growth plate [of the transgenic mice]"  CCN2 enhanced MMP9, Col10a1, VEGF, aggrecan, and Col2a1 expression.

" the enhanced matrix deposition did not result in an increase in the size of the cartilaginous epiphysis; rather, the extended bone length was the result of an elongated bony shaft of the diaphysis."

"Staining of the skeleton of transgenic embryos with type X collagen antibodies indicated that the hypertrophic zone was shorter in the transgenic embryos than in their wt littermates"<-So does CTGF Col2a1 specific overexpression increase adult height or just accelerate growth rate?

"Chondrogenic differentiation of limb-bud mesenchymal cells from CCN2 transgenic animals was greatly enhanced as compared with that of their wild-type counterparts"<-this could result in increased adult height.

Loss of function of CCN2 resulted in impaired endochondral ossification.
According to Magnesium supplementation prevents angiotensin II-induced myocardial damage and CTGF overexpression., in one instance Magnesium inhibited CTGF.

According to Paracrine role for TGF-β-induced CTGF and VEGF in mesangial matrix expansion in progressive glomerular disease., TGF-B induced upregulation of CTGF in one instance.

According to Performance of repetitive tasks induces decreased grip strength and increased fibrogenic proteins in skeletal muscle: role of force and inflammation., exercise can increase CTGF levels.  CTGF seemed to reach maximal levels of 6 weeks of the exercise in the exercise group of a high repetition, minimal force task(target reach rate of 4 reaches/min and <5% maximum pulling force).  The other group with high repetition and high force(target rate of 4 reaches/min and 60% maximum pulling force. ) had higher increases in CTGF and continued even into the 9th week.  The increase in CTGF seemed to be regulated by TNFa and TGFb.  The increase in CTGF was inhibited by anti-inflammatory drugs.

According to Oral glucosamine increases expression of transforming growth factor β1 (TGFβ1) and connective tissue growth factor (CTGF) mRNA in rat cartilage and kidney: implications for human efficacy and toxicity., glucosamine increases CTGF in cartilage.  The increase in CTGF was in articular but not growth cartilage.  It wasn't huge but it was a significant increase 2.3-fold.

In some cases, mechanical load can decrease CTGF by decreasing MMP3.  Cyclic tension increased CTGF expression.

CCN2/CTGF is required for matrix organization and to protect growth plate chondrocytes from cellular stress.

"The loss of CCN2 leads to perinatal lethality resulting from a severe chondrodysplasia. Upon closer inspection of Ccn2 mutant mice, we observed defects in extracellular matrix (ECM) organization and hypothesized that the severe chondrodysplasia caused by loss of CCN2 might be associated with defective chondrocyte survival. Ccn2 mutant growth plate chondrocytes exhibited enlarged endoplasmic reticula (ER), suggesting cellular stress. Immunofluorescence analysis confirmed elevated stress in Ccn2 mutants, with reduced stress observed in Ccn2 overexpressing transgenic mice. In vitro studies revealed that Ccn2 is a stress responsive gene in chondrocytes. The elevated stress observed in Ccn2-/- chondrocytes is direct and mediated in part through integrin α5. The expression of the survival marker NFκB and components of the autophagy pathway were decreased in Ccn2 mutant growth plates, suggesting that CCN2 may be involved in mediating chondrocyte survival. Absence of a matricellular protein can result in increased cellular stress and highlight a novel protective role for CCN2 in chondrocyte survival. The severe chondrodysplasia caused by the loss of CCN2 may be due to increased chondrocyte stress and defective activation of autophagy pathways, leading to decreased cellular survival. These effects may be mediated through nuclear factor κB (NFκB) as part of a CCN2/integrin/NFκB signaling cascade."


"ER enlargement is a hallmark of defective protein folding and cellular stress. ER and other forms of cellular stress activate the Unfolded Protein Response (UPR), an adaptive mechanism to restore cell homeostasis and viability"

"ER stress activates NFκB via tumor necrosis factor-α (TNF-α) receptor associated factor 2 (TRAF2) and inositol requiring enzyme 1 (IRE1) in vitro"

"CCN2 induces NFκB activity in ATDC5 chondrocytic cells through integrin αvβ3-mediated mechanisms to enhance migration"

In this study CCN2 overexpression did not seem to result in increased height in rats. But the structure of the skeletons is different. The growth plate height in CCN2 mice was lower.  The scientists did mention progressive overgrowth of cartilage elements.

CCN2: a master regulator of the genesis of bone and cartilage.

"CCN2 promotes the proliferation and differentiation of growth-plate chondrocytes"

"the over-expression of CCN2 in cartilage stimulated the proliferation and differentiation of growth-plate chondrocytes, resulting in the promotion of endochondral ossification."

Expression of CCN2 can be induced by TGF-Beta.

In this study mice overexpressing CCN2 had longer bones on postnatal day 1.

"In in vitro short-term cultures of chondrocytes prepared from the cartilage of ccn2-over-expressing mice, the expression of col2a1, aggrecan and ccn2 was substantially enhanced; and in long-term cultures the expression levels of these genes were further enhanced"

"IGF-I and IGF-II mRNA levels were elevated in the transgenic chondrocytes, and treatment of non-transgenic chondrocytes with CCN2 stimulated the expression of these mRNAs"

"phosphorylation of ERK1/2 by CCN2 is involved in chondrocyte proliferation, CCN2-BMP-2 treatment might promote chondrocyte differentiation by suppressing chondrocyte proliferation via decreased ERK1/2 phosphorylation."

The role of CCN2 in cartilage and bone development

"CCN2, a classical member of the CCN family of matricellular proteins, is a key molecule that conducts cartilage development in a harmonized manner through novel molecular actions. During vertebrate development, all cartilage is primarily formed by a process of mesenchymal condensation, while CCN2 is induced to promote this process. Afterwards, cartilage develops into several subtypes with different fates and missions, in which CCN2 plays its proper roles according to the corresponding microenvironments. The history of CCN2 in cartilage and bone began with its re-discovery in the growth cartilage in long bones, which determines the skeletal size through the process of endochondral ossification. CCN2 promotes physiological developmental processes not only in the growth cartilage but also in the other types of cartilages, i.e., Meckel’s cartilage representing temporary cartilage without autocalcification, articular cartilage representing hyaline cartilage with physical stiffness, and auricular cartilage representing elastic cartilage. Together with its significant role in intramembranous ossification, CCN2 is regarded as a conductor of skeletogenesis. During cartilage development, the CCN2 gene is dynamically regulated to yield stage-specific production of CCN2 proteins at both transcriptional and post-transcriptional levels. New functional aspects of known biomolecules have been uncovered during the course of investigating these regulatory systems in chondrocytes. Since CCN2 promotes integrated regeneration as well as generation (=development) of these tissues, its utility in regenerative therapy targeting chondrocytes and osteoblasts is indicated, as has already been supported by experimental evidence obtained in vivo."

"CCN2, also known as connective tissue growth factor (CTGF)"

"Meckel’s cartilage arises from mesodermal progenitor cells situated in close proximity to the zone of mineralization during mandibular bone formation"