ECTS Abstracts (2015) 1 OC3.4

Absence of VDR in mature osteoclasts results in enhanced resorptive activity

Yolandi Starczak1, Daniel Reinke3, Rachel Davey2, Howard Morris1, Gerald Atkins3 & Paul Anderson1

1Musculoskeletal Biology Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia; 2Department of Medicine, Austin Health, University of Melnbourne, Melbourne, Australia; 3Centre for Orthopaedics and Trauma Research, University of Adelaide, South Australia, Australia, Adelaide, Australia.

Mature osteoclasts express the vitamin D receptor (VDR) and while we have shown that these cells respond to active vitamin D (1,25(OH)2D3), the role for direct activity of vitamin D in regulating osteoclast function is not well understood. To assess the role for VDR-mediated activity in osteoclasts, osteoclast-specific vitamin D receptor knockout mice (OclVDR−/−) were generated by mating Cathepsin KCre with floxed VDR mice (VDRfl/fl). Male and female OclVDR−/− and VDRfl/fl littermates were assessed at 6 and 12 weeks of age under normal dietary conditions. In addition, isolated splenocytes from global VDRKO mice or their WT littermates were assessed for osteoclast formation, resorption activity and gene expression under osteoclast-forming conditions. 6-weeks-old OclVDR−/− mice demonstrated increased osteoclast surface (Oc.S/BS) in L1 vertebra in both female (+20%, P<0.05) and male (+67%, P<0.05) mice when compared to VDRfl/fl mice. In OclVDR−/− mice, V-ATPase (V0 subunit) mRNA was increased (P<0.05) and Calcitonin Receptor (CTR) mRNA markedly decreased (P<0.05). Despite this, biomarkers such as serum X-laps and TRAP5b were not significantly different between OclVDR−/− and VDRfl/fl mice. Furthermore, only males demonstrated a trend for decreased vertebral BV/TV% due to increase trabecular spacing (Tb.Sp) (P=0.05). Interestingly, RANKL mRNA levels were significantly decreased suggesting reduced signalling for osteoclastogenesis. VDRKO splenocytes cultured under osteoclastogenic conditions resulted in twofold fewer TRAP-positive multinucleated cells (P<0.05) compared with WT cells. However, the resorption area on Osteologic slides was threefold greater per VDRKO osteoclast (P<0.05). VDRKO osteoclast CTR mRNA levels associated with reduced Bax/Bcl mRNA ratio were markedly decreased compared with WT suggesting resistance to apoptosis. Thus, while vitamin D receptor expressed within haematopoietic precursor cells may not be required for differentiation of osteoclasts, the role for VDR in mature osteoclasts appears to be to attenuate resorptive activity.

Disclosure: The authors declared no competing interests. This work was supported by National Health and Medical Research Council (NHMRC) APP1029926, 2012-2014.

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