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

•The deletion of vitamin D receptor in osteoclasts results in femoral bone loss.•Osteoclast-specific VDRKO mice exhibit a marked reduction in thin trabeculae bone following OVX.•Osteoclast-specific VDRKO mice exhibited enhanced expression of osteoclast markers of activity in in vitro cultures. 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 Vdrfl/fl or Cyp27b1fl/fl mice with Cathepsin K-Cre transgenic mice (CstkCre) to generate CtskCre/Vdr−/− and CtskCre/Cyp27b1−/− mice respectively. To account for potential CtskCre-meaited off-target deletion of Vdr, Dmp1Cre were also used determine the effect of Vdr deletion in osteocytes. Furthermore, CtskCre/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 CtskCre/Vdr−/− female mice demonstrated a 15% decrease in femoral BV/TV (p