Osteocyte Death and Bone Overgrowth in Mice Lacking Fibroblast Growth Factor Receptors 1 and 2 in Mature Osteoblasts and Osteocytes

Jennifer McKenzie, Craig Smith, Kannan Karuppaiah, Joshua Langberg, Matthew J. Silva, David M. Ornitz

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Fibroblast growth factor (FGF) signaling pathways have well-established roles in skeletal development, with essential functions in both chondrogenesis and osteogenesis. In mice, previous conditional knockout studies suggested distinct roles for FGF receptor 1 (FGFR1) signaling at different stages of osteogenesis and a role for FGFR2 in osteoblast maturation. However, the potential for redundancy among FGFRs and the mechanisms and consequences of stage-specific osteoblast lineage regulation were not addressed. Here, we conditionally inactivate Fgfr1 and Fgfr2 in mature osteoblasts with an Osteocalcin (OC)-Cre or Dentin matrix protein 1 (Dmp1)-CreER driver. We find that young mice lacking both receptors or only FGFR1 are phenotypically normal. However, between 6 and 12 weeks of age, OC-Cre Fgfr1/Fgfr2 double- and Fgfr1 single-conditional knockout mice develop a high bone mass phenotype with increased periosteal apposition, increased and disorganized endocortical bone with increased porosity, and biomechanical properties that reflect increased bone mass but impaired material properties. Histopathological and gene expression analyses show that this phenotype is preceded by a striking loss of osteocytes and accompanied by activation of the Wnt/β-catenin signaling pathway. These data identify a role for FGFR1 signaling in mature osteoblasts/osteocytes that is directly or indirectly required for osteocyte survival and regulation of bone mass during postnatal bone growth.

Original languageEnglish
Pages (from-to)1660-1675
Number of pages16
JournalJournal of Bone and Mineral Research
Volume34
Issue number9
DOIs
StatePublished - Sep 1 2019

Keywords

  • APOPTOSIS
  • FIBROBLAST GROWTH FACTORS
  • MOLECULAR PATHWAYS-REMODELING
  • OSTEOBLASTS
  • OSTEOCYTES

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