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, Leigh Quarles

Research output: Contribution to journalArticle

48 Citations (Scopus)

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 - Jul 4 2012

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Metabolic Bone Diseases
Osteoblasts
Osteogenesis
Hedgehogs
Cilia
Osteocalcin
Calcium
Bone and Bones
T Cell Transcription Factor 1
Catenins
Adipogenesis
Thigh
Bone Density
Minerals
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Cell Biology

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Disruption of Kif3a in osteoblasts results in defective bone formation and osteopenia. / Qiu, Ni; Xiao, Zhousheng; Cao, Li; Buechel, Meagan M.; David, Valentin; Roan, Esra; Quarles, Leigh.

In: Journal of Cell Science, Vol. 125, No. 8, 04.07.2012, p. 1945-1957.

Research output: Contribution to journalArticle

Qiu, Ni ; Xiao, Zhousheng ; Cao, Li ; Buechel, Meagan M. ; David, Valentin ; Roan, Esra ; Quarles, Leigh. / Disruption of Kif3a in osteoblasts results in defective bone formation and osteopenia. In: Journal of Cell Science. 2012 ; Vol. 125, No. 8. pp. 1945-1957.
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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.",
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