Imranul Alama, Mohammed Alkhoulia, Rita L. Gerard-O’Rileya, Weston B. Wrighta, Dena Actona, Amie K. Graya, Bhavmik Patela, Austin M. Reillya, Kyung-Eun Limc, Alexander G. Roblingc, and Michael J. Econs
Previous genome-wide association studies have identified common variants in genes associated with bone mineral density (BMD) and risk of fracture. Recently, we identified SNPs in WNT16 that were associated with peak BMD in premenopausal women. To further identify the role of Wnt16 in bone mass regulation, we created transgenic (TG) mice over-expressing human WNT16 in osteoblasts. We compared bone phenotypes, serum biochemistry, gene expression and dynamic bone histomorphometry between TG and wild-type (WT) mice. Compared to WT mice, WNT16-TG mice exhibited significantly higher whole body aBMD and BMC at 6 and 12 weeks of age in both male and female. Micro-CT analysis of trabecular bone at distal femur revealed 3-fold (male) and 14-fold (female) higher BV/TV, and significantly higher Tb.N, Tb.Th but lower Tb.Sp in TG mice compared to WT littermates in both sexes. Serum biochemistry analysis showed that male TG mice had higher serum ALP, OC, OPG, OPG/RANKL ratio as compared to WT mice. Also, lower CTX/TRAPc5b ratio was observed in TG mice compared to WT littermates in both male and female. Histomorphometry data demonstrated that both male and female TG mice had significantly higher cortical and trabecular MS/BS and BFR compared to sex-matched wild-type mice. Gene expression analysis demonstrated higher expression of Alp, OC, Opg, Opg/Rankl ratio in bone tissue in the transgenic mice compared to wild-type littermates. Our data indicate that WNT16 is critical for positive regulation of both cortical and trabecular bone mass and structure, and that this molecule might be targeted for therapeutic interventions to treat osteoporosis.