Mechanism of Bone Growth : Research on proliferation and apoptosis of growth plate chondrocyte.

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We aimed to explore molecular basis of the cell proliferation, differentiation, and cell death(apoptosis) of the growth plate chondrocyte in this project. To this aid, we selected achondroplasia as a model disorder of growth plate chondrocyte. The responsible gene to this disorder is the gene coding fibroblast growth factor receptor 3 (FGFR3). The major mutation is G380R, which activate receptor constitutively. And related severe form, thanatophoric dysplasia is due to the mutation, K650E, which induce receptor activation more profoundly. We at first introduced these mutations into chondrogenic cell line, ATDC5, and studied phenotypic change of these cells. The chondrocytes expressing mutated FGFR3 showed deteriorated cell growth and increased apoptosis. The inhibition of the cell growth was mediated by the activation of p21 and increased apoptosis was due to the decreased bcl-2 expression. Moreover K650E mutation induced stat 1 activation and its nuclear translocation and this event l … More ooked to located upstream of deteriorated cell growth and increased apoptosis. IGF-I induced by the Growth hormone treatment may activate PI3K and then increase bcl-2 expression. This mechanism may be responsible to the rescue chondrocyte from apoptosis and to GH stimulated bone growth in achondroplasia.From thee analogy of achondroplasia to PTHrP KO mice, we next studied PTHrP expression in this cellular model. The cells expressing mutated FGFR3 showed decreased expression of PTHrP mRNA. Moreover, this decrease was more severe in K650E mutation. Next we administered PTHrP to the cells by several methods and confirmed that PTHrP signal may blockk pathogenic pathway induced by constitutively activated FGFR3 and rescue the cells from apoptosis. Bone organ culture system using cartilage specific mutated FGFR3 transgenic mice showed increased bone length, which was mainly due to the expansion of proliferative chondrocyte zone. In vivo experiment similarly indicates promising effect of PTH on the bone growth of achondroplasia. Less