Disruption of Kif3a in osteoblasts results in defective bone formation and osteopenia

Ni Qiu, Zhousheng Xiao*, Li Cao, Meagan M. Buechel, Valentin David, Esra Roan, L. Darry Quarles

*Corresponding author for this work

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

We investigated whether Kif3a in osteoblasts has a direct role in regulating postnatal bone formation. We conditionally deleted Kif3a in osteoblasts by crossing osteocalcin (Oc; also known as Bglap)-Cre with Kif3aflox/null mice. Conditional Kif3a-null mice (Kif3aOc-cKO) had a 75% reduction in Kif3a transcripts in bone and osteoblasts. Conditional deletion of Kif3a resulted in the reduction of primary cilia number by 51% and length by 27% in osteoblasts. Kif3aOc-cKO mice developed osteopenia by 6 weeks of age unlike Kif3aflox/+ control mice, as evidenced by reductions in femoral bone mineral density (22%), trabecular bone volume (42%) and cortical thickness (17%). By contrast, Oc-Cre;Kif3aflox/+ and Kif3aflox/null heterozygous mice exhibited no skeletal abnormalities. Loss of bone mass in Kif3aOc-cKO mice was associated with impaired osteoblast function in vivo, as reflected by a 54% reduction in mineral apposition rate and decreased expression of Runx2, osterix (also known as Sp7 transcription factor 7; Sp7), osteocalcin and Dmp1 compared with controls. Immortalized osteoblasts from Kif3aOc-cKO mice exhibited increased cell proliferation, impaired osteoblastic differentiation, and enhanced adipogenesis in vitro. Osteoblasts derived from Kif3aOc-cKO mice also had lower basal cytosolic calcium levels and impaired intracellular calcium responses to fluid flow shear stress. Sonic hedgehog-mediated Gli2 expression and Wnt3a-mediated β-catenin and Axin2 expression were also attenuated in Kif3aOc-cKO bone and osteoblast cultures. These data indicate that selective deletion of Kif3a in osteoblasts disrupts primary cilia formation and/or function and impairs osteoblast-mediated bone formation through multiple pathways including intracellular calcium, hedgehog and Wnt signaling.

Original languageEnglish (US)
Pages (from-to)1945-1957
Number of pages13
JournalJournal of cell science
Volume125
Issue number8
DOIs
StatePublished - 2012

Keywords

  • Bone formation
  • Conditional deletion
  • Kif3a
  • Osteoblast functions
  • Primary cilia
  • Signaling

ASJC Scopus subject areas

  • Cell Biology

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    Qiu, N., Xiao, Z., Cao, L., Buechel, M. M., David, V., Roan, E., & Quarles, L. D. (2012). Disruption of Kif3a in osteoblasts results in defective bone formation and osteopenia. Journal of cell science, 125(8), 1945-1957. https://doi.org/10.1242/jcs.095893