Impaired osteoclastogenesis in conditional osteoblast VDR-KO mice results in exacerbated PTH-mediated bone catabolism under suboptimal dietary conditions. — ASN Events
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Impaired osteoclastogenesis in conditional osteoblast VDR-KO mice results in exacerbated PTH-mediated bone catabolism under suboptimal dietary conditions. (#102)

Jackson W Ryan 1 , Rahma Triliana 2 , Rebecca K Sawyer 1 , Michele V Clarke 3 , Kate R Barratt 1 , Patricia K Russell 3 , Gerald J Atkins 2 , Rachel A Davey 3 , Howard A Morris 1 , Paul H. Anderson 1
  1. University of South Australia, Adelaide, SA, Australia
  2. University of Adelaide, Adelaide, SA, Australia
  3. University of Melbourne, Melbourne, Vic, Australia

Vitamin D is essential for maintaining normal serum calcium levels. In this context, vitamin D is well known to enhance bone resorption via RANKL-mediated osteoclastogenesis. What is less clear is the relative contribution that osteoblastic vitamin D receptor (VDR) plays in regulating bone catabolism under suboptimal dietary conditions. We have generated 6w female osteoblast-specific VDRKO mice (OsteocalcinCre+/Vdrfl/fl) mice which display pronounced reductions in Rankl mRNA, metaphyseal Oc.Sur/BS and serum X-laps. As a consequence, trabecular BV/TV% was increased in the femur (19%, p<0.05) and vertebra (21%, p<0.05) in comparison to littermate controls. However, when weanling female OsteocalcinCre+/Vdrfl/fl mice were subjected to a low calcium/phosphorus diet (0.03%/0.08%; LowCa/P) for 3w, abrogation of the bone volume to control mice levels occurred. Furthermore, serum PTH, 1,25D and x-laps levels were markedly elevated over levels in LowCa/P-fed control mice, suggesting exacerbated bone catabolism as a consequence of absent VDR signalling in osteoblasts.  When the LowCa/P diet was continued to 20w of age in OsteocalcinCre+/Vdrfl/fl mice, the excessive PTH and 1,25D persisted, resulting in major deleterious effects on trabecular and cortical bone including stunted growth, disorganised growth plate and marked intra-cortical porosity.  In contrast, when 17w-old OsteocalcinCre+/Vdrfl/fl mice commenced the LowCa/P diet for 3 weeks, no elevation in PTH was observed suggesting that the absence of VDR activity in mature osteoblasts impacts on feed-back on PTH release only in growing mice. Collectively, these data suggest that mature osteoblasts play a significant role in VDR-mediated bone resorption in young mice. Furthermore, these data suggest that that consequence of impaired vitamin D-mediated bone resorption can result in inappropriately high PTH-mediated bone resorption, under suboptimal dietary conditions. Thus, in this context, vitamin D-mediated bone resorption ensures sufficient calcium release to prevent an overt PTH response with greater negative skeletal consequences.