ECTS Abstracts (2015) 1 OC3.3

Transgenic over-expression of vitamin D receptor in mature osteoblasts enhances catabolic activities under dietary calcium and phosphorus restriction

Rahma Triliana1,2, Rebecca Sawyer3, Howard Morris2,3 & Paul Anderson2,3

1Faculty of Medicine, Islamic University of Malang, Malang, East Java, Indonesia; 2School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia; 3School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.

Osteoblast-specific over-expression of vitamin D receptor (VDR) in a transgenic mouse on a FVB/N genetic background (OSVDR) increases bone volume due to both reduced RANKL-mediated osteoclastic bone resorption and enhanced bone formation. These observations are in contrast to reports of 1,25-dihydroxyvitamin D (1,25D) enhancing osteoclastic bone resorption and inhibiting bone mineralisation. To address this conundrum, 3 weeks female mice with osteoblast-specific over-expression of vitamin D receptor (VDR) (ObVDR-Tg), osteoblast-specific VDRKO (ObVDR-KO) and littermate control mice (WT, VDRfl/fl) all on a C57/Bl6 genetic background were fed calcium/phosphorus restricted diet (0.03% Ca, 0.08% Phos; LowCa/P) for 17 weeks and compared with a normal diet (1% Ca, 0.625% Phos; NormCa/P). ObVDR-Tg mice fed the NormCa/P diet demonstrated increased trabecular (64% P<0.01) and cortical bone volumes (8%, P=0.056) when compared with WT mice with increased periosteal circumference (P<0.05). All mice fed the LowCa/P diet resulted in marked osteopenia with almost total absence of metaphyseal trabecular bone. However, LowCa/P fed ObVDR-Tg mice maintained the increased periosteal circumference, whereas LowCa/P fed ObVDR-KO mice decreased periosteal circumference. Furthermore, LowCa/P fed ObVDR-Tg increased the endosteal circumference, whereas LowCa/P fed ObVDR-KO decreased the endosteal circumference. Interestingly, LowCa/P fed ObVDR-Tg mice exhibited marked intra-cortical porosity and a 22% reduction in cortical osteocyte density. While, serum calcium and phosphorus levels were unaltered in LowCa/P fed ObVDR-Tg mice, serum FGF23 levels were twofold lower and serum 1,25D levels were twofold higher when compared with WT mice. In addition, RANKL mRNA levels and RANKL:OPG ratio were markedly raised in LowCa/P fed ObVDR-Tg mice. Thus, while overexpression of VDR in osteoblasts can mediate anabolic activities, under conditions of limited dietary calcium and phosphorus, profound bone catabolism prevails possibly due to a lack of appropriate FGF23 feed-back on renal 1,25D synthesis and enhanced RANKL-mediated catabolism.

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). PhD scholarship for Rahma Triliana is provided by the Directorate General of Higher Education (DGHE/DIKTI), the Government of Indonesia.

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