Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3

Fibroblast growth factor receptor 3 (FGFR3) is a key regulator of skeletal growth and activating mutations in Fgfr3 cause achondroplasia, the most com mon genetic form of dwarfism in humans. Little is known about the mechanism by which FGFR3 inhibits bone growth and how FGFR3 signaling interacts with other signaling pathways that regulate endochondral ossification. To under stand these mechanisms, we targeted the expression of an activated FGFR3 to growth plate cartilage in mice using regulatory elements from the collagen II gene. As with humans carrying the achondroplasia mutation, the resultin g transgenic mice are dwarfed, with axial, appendicular and craniofacial sk eletal hypoplasia, We found that FGFR3 inhibited endochondral bone growth b y markedly inhibiting chondrocyte proliferation and by slowing chondrocyte differentiation, Significantly, FGFR3 do downregulated the Indian hedgehog (Ihh) signaling pathway and Bmp4 expression in both growth plate chondrocyt es and in the perichondrium. Conversely, Bmp4 expression is upregulated in the perichondrium of Fgfr3(-/-) mice. These data support a model in which F gfr3 is an upstream negative regulator of the hedgehog (Hh) signaling pathw ay Additionally, Fgfr3 may coordinate the growth and differentiation of cho ndrocytes with the growth and differentiation of osteoprogenitor cells by s imultaneously modulating Bmp4 and patched expression in both growth plate c artilage and in the perichondrium.