Absence of vitamin D receptor in mature osteoclasts results in altered osteoclastic activity and bone loss

作者：Starczak Yolandi; Reinke Daniel C; Barratt Kate R; Ryan Jackson W; Russell Patricia K; Clarke Michele V; St Arnaud Rene; Morris Howard A; Davey Rachel A; Atkins Gerald J; Anderson Paul H^*

来源：Journal of Steroid Biochemistry and Molecular Biology, 2018, 177: 77-82.

DOI：10.1016/j.jsbmb.2017.10.022

• Osteoclast
• Osteoclastogenesis
• Vitamin D
• Vitamin D receptor
• CYP27B1

Mature osteoclasts express the vitamin D receptor (VDR) and are able to synthesise and respond to 1,25(OH)(2)D-3 via CYP27B1 enzyme activity. Whether vitamin D signalling within osteoclasts is necessary for the regulation of osteoclastic bone resorption in an in vivo setting is unclear. To determine the requirement for the VDR- and CYP27B1-mediated activity in mature osteoclasts, conditional deletion mouse models were created whereby either Vdr or Cyp27b1 gene was inactivated by breeding either Vdr(fl/fl) or Cyp27b1(fl/fl) mice with Cathepsin K-Cre transgenic mice (Cstk(Cre)) to generate Ctsk(Cre)/Vdr(-/-) and Ctsk(Cre)/Cyp27b1(-/-) mice respectively. To account for potential Ctsk(Cre)-meaited off-target deletion of Vdr, Dmpl(Cre) were also used determine the effect of Vdr deletion in osteocytes. Furthermore, Ctsk(Cre)/Vdr(-/-) mice were ovariectomised (OVX) to assess the role of VDR in osteoclasts under bone-loss conditions and bone marrow precursor cells were cultured under osteoclastogenic conditions to assess osteoclast formation. Six-week-old Ctsk(Cre)/Vdr(-/-) female mice demonstrated a 15% decrease in femoral BV/TV (p < 0.05). In contrast, BV/TV remained unchanged in Ctsk(Cre)/Cyp27b1(-/-) mice as well as in Dmpl(Cre)/VDR-/- mice. When Ctsk(Cre)/Vdr(-/-) mice were subjected to OVX, the bone loss that occurred in Ctsk(Cre)/Vdr(-/-) was predominantly due to a diminished volume of thinner trabeculae when compared to control levels. These changes in bone volume in Ctsk(Cre)/Vdr(-/-) mice occurred without an observable histological change in osteoclast numbers or size. However, while cultured bone marrow-derived osteoclasts from Ctsk(Cre)/Vdr(-/-) mice were marginally increased when compared to VDRfl/fl mice, elevated expression of genes such as Cathepsin K, Nfatcl and VATPase was observed. Collectively, these data indicate that the absence of VDR in mature osteoclasts causes exacerbated bone loss in young mice and during OVX which is associated with enhanced osteoclastic activity and without increased osteoclastogenesis.

• 出版日期2018-3
• 单位McGill