Functional analysis of the cartilage-derived multifunctional growth factor ecogenin/CTGF by using mutant animals

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1) We established transgenic mice that overproduce ecogenin/CTGF under the control of mouse type IX collagen promoter. The mice showed dwarfism and decreases bone density. The expression of ctgf was completely abolished in cbfal -nul I mice, ctgf-transgenic mice rescued the cartilage differentiation of cbfal-null mice.2) We examined the phenotype of ctgf null mice provided in collaboration with K. Layons and found that they had the disorders of not only endochondral ossification but also tooth development.3) Ecogenin/CTGF promoted proliferation and proteogycan synthesis of articular chondrocytes but did not promote their hypertrophy. It also repaired articular cartilage defect without calcification. Ecogenin/CTGF induced chondrocyte differentiation though p38 MAPK, and chondrocyte proliferation through ERK. Perlecan was essential for the paracrine action of ecogenin/CTGF on chondrocytes. Moreover, ecogenin/CTGF was found to bind actin and to induce apoptosis when overexpressed, suggesting intracellular function. Therefore, the high level of gene expression of ecogenin/CTGF in hypertrophic chondrocytes may be related to their cell death at the end of endochondral ossification, in addition to the role as a paracrine factor. We also found tahat ecogenin/CTGF is one of hypoxia-induced angiogenesis factors. We also found cis-element which regulates ecogenin/CTGF in chondrocytes.4) Expression of ecogenin/CTGF was observed in not only in hypertrophic chpndrcoyes but also in osteoblas and pre-osteoblats during fracture healing. Its gene expression was also observed in osteoblasts during alveolar bone regeneration after tooth extraction. Mechanical stress induced gene expression of ecogenin/CTGF in osteoblasts and osteocytes.These findings indicates that ecogenin/CTGF is a multifunctional growth factor which play important roles in endochondral ossification, intramembranous ossification, tooth development, maintainance and repair of articular cartilage and bone remodeling.