Expression of FGFR3 with the G380R achondroplasia mutation inhibits proliferation and maturation of CFK2 chondrocytic cells

A G380R substitution in the transmembrane-spanning region of FGFR3 (FGFR3(A ch)) results in constitutive receptor kinase activity and is the most commo n cause of achondroplastic dwarfism in humans. The epiphyseal growth plates of affected individuals are disorganized and hypocellular and show aberran t chondrocyte maturation. To examine the molecular basis of these abnormali ties, we used a chondrocytic cell line, CFK2, to stably express the b varia nt of wild-type FGFR3 or the the constitutively active FGFR3(Ach). Overexpr ession of FGFR3 had minimal effects on CFK2 proliferation and maturation co mpared with the severe growth retardation found in cells expressing FGFR3(A ch). Cells expressing the mutant receptor also showed an abnormal apoptotic response to serum deprivation and failed to undergo differentiation under appropriate culture conditions. These changes were associated with altered expression of integrin subunits, which effectively led to a switch in subst rate preference of the immature cell from fibronectin to type II collagen. These in vitro observations support those from in vivo studies indicating t hat FGFR3 mediates an inhibitory influence on chondrocyte proliferation. We now suggest that the mechanism is related to altered integrin expression.