FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth

Kannan Karuppaiah, Kai Yu, Joohyun Lim, Jianquan Chen, Craig Smith, Fanxin Long, David M. Ornitz

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

Fibroblast growth factor (FGF) signaling is important for skeletal development; however, cell-specific functions, redundancy and feedback mechanisms regulating bone growth are poorly understood. FGF receptors 1 and 2 (Fgfr1 and Fgfr2) are both expressed in the osteoprogenitor lineage. Double conditional knockout mice, in which both receptors were inactivated using an osteoprogenitor-specific Cre driver, appeared normal at birth; however, these mice showed severe postnatal growth defects that include an ~ 50%reduction in bodyweight and bone mass, and impaired longitudinal bone growth. Histological analysis showed reduced cortical and trabecular bone, suggesting cellautonomous functions of FGF signaling during postnatal bone formation. Surprisingly, the double conditional knockout mice also showed growth plate defects and an arrest in chondrocyte proliferation. We provide genetic evidence of a non-cell-autonomous feedback pathway regulating Fgf9, Fgf18 and Pthlh expression, which led to increased expression and signaling of Fgfr3 in growth plate chondrocytes and suppression of chondrocyte proliferation. These observations show that FGF signaling in the osteoprogenitor lineage is obligately coupled to chondrocyte proliferation and the regulation of longitudinal bone growth.

Original languageEnglish
Pages (from-to)1811-1822
Number of pages12
JournalDevelopment (Cambridge)
Volume143
Issue number10
DOIs
StatePublished - May 15 2016

Keywords

  • Chondrocyte
  • Endochondral bone formation
  • FGF signaling
  • IHH
  • Mouse
  • Osteoblast
  • PTHLH
  • Skeletal development

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