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 (FGFR3Ach) results in constitutive receptor kinase activity and is the most common cause of achondroplastic dwarfism in humans. The epiphyseal growth plates of affected individuals are disorganized and hypocellular and show aberrant chondrocyte maturation. To examine the molecular basis of these abnormalities, we used a chondrocytic cell line, CFK2, to stably express the b variant of wild-type FGFR3 or the the constitutively active FGFR3Ach. Overexpression of FGFR3 had minimal effects on CFK2 proliferation and maturation compared with the severe growth retardation found in cells expressing FGFR3Ach. 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 substrate preference of the immature cell from fibronectin to type II collagen. These in vitro observations support those from in vivo studies indicating that FGFR3 mediates an inhibitory influence on chondrocyte proliferation. We now suggest that the mechanism is related to altered integrin expression.
Henderson
J E
JE
Lady Davis Institute for Medical Research, Division of Enodcrinology and Geriatrics, Sir Mortimer B. Davis-Jewish General Hospital, Canada.
Naski
M C
MC
Aarts
M M
MM
Wang
D
D
Cheng
L
L
Goltzman
D
D
Ornitz
D M
DM
D000130:Achondroplasia / Q000235:genetics*; D000199:Actins / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002448:Cell Adhesion; D002454:Cell Differentiation / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology*; D017931:DNA Primers; D016023:Integrins / Q000378:metabolism; D009154:Mutation; D011505:Protein-Tyrosine Kinases; D051381:Rats; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics* / Q000378:metabolism
D000199:Actins; D017931:DNA Primers; D016023:Integrins; D017468:Receptors, Fibroblast Growth Factor; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3