Monday, September 19, 2011

juvenile versus adult articular cartilage gene expression

What genes are expressed differently in the articular cartilage and how can that impact height growth?

Enhanced Tissue Regeneration Potential of Juvenile Articular Cartilage.

"Articular cartilage harvested from juvenile (age, 4 months) and adult (age, 6-8 years) bovine femoral condyles was cultured for 4 weeks to monitor chondrocyte migration, glycosaminoglycan content conservation, and new tissue formation. The cartilage cell density and proliferative activity were also compared.  Compared with adult cartilage, juvenile bovine cartilage demonstrated a significantly greater cell density, higher cell proliferation rate, increased cell outgrowth, elevated glycosaminoglycan content, and enhanced matrix metallopeptidase 2{up} activity. During 4 weeks in culture, only juvenile cartilage was able to generate new cartilaginous tissues, which exhibited pronounced labeling for proteoglycan and type II collagen but not type I collagen. With over 19,000 genes analyzed, distinctive gene expression profiles were identified. The genes mostly involved in cartilage growth and expansion, such as COL2A1{up}, COL9A1{up}, MMP2{up}, MMP14{up}, and TGFB3, were upregulated in juvenile cartilage, whereas the genes primarily responsible for structural integrity, such as COMP, FN1, TIMP2, TIMP3, and BMP2{up}, were upregulated in adult cartilage. As the first comprehensive comparison between juvenile and adult bovine articular cartilage at the tissue, cellular, and molecular levels, the results strongly suggest that juvenile cartilage possesses superior chondrogenic activity and enhanced regenerative potential over its adult counterpart. Additionally, the differential gene expression profiles of juvenile and adult cartilage suggest possible mechanisms underlying cartilage age-related changes in their regeneration capabilities, structural components, and biological properties."

"It appeared that numerous juvenile chondrocytes were able to break down the matrix entrapment in their migrating front, forming migration channels. Through these channels, the juvenile chondrocytes that resided far away from the cut margins were able to migrate out. However, these channels were not observed from adult cartilage, as the migrating adult chondrocytes mostly resided adjacent to the cut edges of the cartilage discs"

Another gene upregulated in juvenile articular cartilage is IGF2.

"breakdown of the collagen network by extensive cutting has been shown to promote chondrocyte migration"<-Maybe we can cause migration of the chondrocytes to form new growth plates?

"abundant open surfaces of the cartilage discs may provide a permissive environment, allowing the “passive” migration of the chondrocytes residing adjacent to the cut margins in both age groups. Juvenile chondrocytes, however, appeared to migrate in a more active manner by breaking down the local ECM network at their migrating front. These different migration activities could be explained by our GeneChip array findings. As a cell membrane–anchored enzyme, MMP14 has been reported to localize at the migration front and promote cell migration by cleaving the cellular adhesion molecule CD44 and triggering MMP activation cascades. Because MMP2, MMP13, MMP14, and MMP16 were all upregulated in juvenile cartilage and the overexpression of MMP2 was further confirmed by both qPCR and MMP2 activity assays, we hypothesize that the migration of juvenile chondrocytes is facilitated by a MMP activation cascade wherein MMP14 activates pro-MMP2, which in turn activates pro-MMP13. As a broad-spectrum ECM-destructing enzyme, MMP13, whose expression was 1.6-fold higher in juvenile cartilage, cleaves local type II collagen, aggrecan, and pericellular ECM components. As a result, activation of these juvenile cartilage upregulated MMPs not only increases chondrocyte mobility by detaching them from the surrounding ECM but also opens up a migration pathway by digesting their pericellular ECM barriers."

" adult cartilage expresses elevated levels of TIMP2 and TIMP3, which block the MMP activation cascade, leading to the inhibition of “active” chondrocyte migration."

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