Active vitamin D (1,25D), bound to the vitamin D receptor (VDR), can directly regulate osteoblast activity modulating bone resorption via induction of RANKL. However, it is somewhat unclear as to which cells of the osteoblast lineage are predominantly responsible for this activity. We have generated mature osteoblast-VDR knock out (mOb-VDRKO) mice using an osteocalcin promoter-Cre to demonstrate the role of VDR-mediated bone resorption in mature osteoblasts during growth and under dietary calcium/phosphorus restriction. 6 week old female mOb-VDRKO mice displayed a pronounced reduction in RANKL mRNA expression, metaphyseal osteoclast surface (OcSur/BS) and serum X-laps. As a consequence, trabecular bone volume (BV/TV%) was increased in the femur (19%, P<0.05) and vertebra (21%, P<0.05) in comparison to littermate controls. The increase in trabecular bone in female mOb-VDRKO persisted at 12 week of age but was absent by 26 week of age. By comparison, 6-week-old female osteocyte-specific-VDRKO mice (deletion driven by Dmp1-Cre), exhibited no structural differences in femoral trabecular BV/TV%, and unchanged OcSur/BS. However, vertebral BV/TV% was modestly increased (8%, P<0.05) in Oy-VDRKO mice. When 3-week-old female mOb-VDRKO mice were subjected to a low calcium (0.03%) and phosphorus diet (0.08%) (LowCa/P) for 3 weeks, serum PTH levels and X-laps levels were approximately twofold greater than LowCa/P fed control mice, resulting in the abrogation of the bone phenotype to levels comparable to control mice. When the LowCa/P was continued to 20 weeks of age, higher serum PTH and X-laps levels persisted in mOb-VDRKO mice resulting in deleterious effects on bone including significant intra-cortical porosity. Collectively, these data suggest that mature osteoblasts play a greater role in VDR-mediated bone resorption than osteocytes in young mice. Furthermore, the absence of VDR in mature osteoblasts during calcium/phosphorus restriction results in inappropriately high PTH-mediated bone resorption, possibly through lack of appropriate VDR-mediated bone resorption.
Disclosure: The authors declared no competing interests. This work was supported by a Project Grant from the National Health and Medical Research Council, Australia (APP1003433) and Career Development Fellowship for P.A. (APP1034698).