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

Publication date: Available online 28 October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Yolandi Starczak, Daniel C. Reinke, Kate R. Barratt, Jackson W. Ryan, René St-Arnaud, Howard A. Morris, Rachel A. Davey, Gerald J. Atkins, Paul H. Anderson
Mature osteoclasts express the vitamin D receptor (VDR) and are able to synthesise and respond to 1,25(OH)2D3 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, Dmp1^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 Dmp1^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 VDR^fl/fl mice, elevated expression of genes such as Cathepsin K, Nfatc1 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.



http://ift.tt/2h6kypv