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

利用突变动物对软骨源性多功能生长因子 Ecogenin/CTGF 进行功能分析

基本信息

批准号：
13307053
负责人：
TAKIGAWA Masaharu
金额：
$ 23.71万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

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.

1)在小鼠IX型胶原启动子的控制下，建立了高表达Ecogenin/CTGF的转基因小鼠。这些小鼠表现出侏儒症和骨密度下降。在cbfal-nul小鼠中CTGF的表达完全消失，CTGF转基因小鼠挽救了cbfal基因缺失小鼠的软骨分化。2)我们检测了与K.Layons联合提供的CTGF基因缺失小鼠的表型，发现它们不仅存在软骨内成骨障碍，还存在牙齿发育障碍。3)Ecogenin/CTGF促进关节软骨细胞的增殖和蛋白聚糖的合成，但不促进其肥大。修复关节软骨缺损区，无钙化。Ecogenin/CTGF通过p38MAPK诱导软骨细胞分化，通过ERK诱导软骨细胞增殖。Perlecan在Ecogenin/CTGF对软骨细胞的旁分泌作用中起重要作用。此外，Ecogenin/CTGF被发现在过表达时结合肌动蛋白并诱导细胞凋亡，提示细胞内功能。因此，肥大软骨细胞中Ecogenin/CTGF基因的高水平表达除了作为旁分泌因子的作用外，可能还与软骨内成骨末期细胞死亡有关。我们还发现Tahat ecgenin/CTGF是低氧诱导的血管生成因子之一。4)在骨折愈合过程中，不仅在肥大的软骨细胞中观察到Ecogenin/CTGF的表达，而且在成骨细胞和成骨细胞中也观察到了Ecogenin/CTGF的表达。在拔牙后牙槽骨再生过程中，其基因在成骨细胞中也有表达。机械应力诱导成骨细胞和成骨细胞表达Ecogenin/CTGF基因，提示Ecogenin/CTGF是一种多功能的生长因子，在软骨内成骨、膜内成骨、牙齿发育、关节软骨的维持和修复以及骨重建等过程中发挥重要作用。