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

Janet E. Henderson, Michael C. Naski, Michelle M. Aarts, Dashen Wang, Li Cheng, David Goltzman, David M. Ornitz

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

A G380R substitution in the transmembrane-spanning region of FGFR3 (FGFR3(Ach)) 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 FGFR3(Ach). Overexpression of FGFR3 had minimal effects on CFK2 proliferation and maturation compared with the severe growth retardation found in cells expressing FGFR3(Ach). 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.

Original languageEnglish
Pages (from-to)155-165
Number of pages11
JournalJournal of Bone and Mineral Research
Volume15
Issue number1
DOIs
StatePublished - 2000

Keywords

  • Apoptosis
  • Chondrocyte
  • FGFR3(Ach)
  • Integrins
  • Maturation
  • Proliferation

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