Differential regulation of endochondral bone growth and joint development by FGFR1 and FGFR3 tyrosine kinase domains

Fibroblast growth factor receptors (FGFR) 1 and 3 have distinct mitogenic a ctivities in vitro. In several cultured cell lines, FGFR1 transmits a poten t mitogenic signal, whereas FGFR3 has little or no mitogenic activity. Howe ver, in other in vitro assays the FGFR3 intracellular domain is comparable with that of FGFR1. In vivo, FGFR3 negatively regulates chondrocyte prolife ration and differentiation, and activating mutations are the molecular etio logy of achondroplasia. By contrast, FGFR1 transmits a proliferative signal in various cell types in vivo. These observations suggest that inhibition of the proliferating chondrocyte could be a unique property of FGFR3 or, al ternatively, a unique property of the proliferating chondrocyte. To test th is hypothesis, FGFR1 signaling was activated in the growth plate in cells t hat normally express FGFR3. Comparison of transgenic mice with an activated FGFR1 signaling pathway with an achondroplasia-like mouse that expresses a similarly activated FGFR3 signaling pathway demonstrated that both transge nes result in a similar achondroplasia-like dwarfism. These data demonstrat e that suppression of mitogenic activity by FGFR signaling is a property th at is unique to growth plate chondrocytes. Surprisingly, we observed that i n transgenic mice expressing an activated FGFR, some synovial joints failed to develop and were replaced by cartilage. The defects in the digit joints phenocopied the symphalangism that occurs in Apert syndrome and the number of affected joints was dependent on transgene dose. In contrast to the phe notype in the growth plate, the joint phenotype was more severe in transgen ic mice with an activated FGFR1 signaling pathway. The failure of joint dev elopment resulted from expanded chondrification in the presumptive joint sp ace, suggesting a crucial role for FGF signaling in regulating the transiti on of condensed mesenchyme to cartilage and in defining the boundary of ske letal elements.