Abstract
Recently, we demonstrated that osteoblast-specific overexpression of human WNT16 increased both cortical and trabecular bone mass and structure in mice. To further identify the cell-specific role of Wnt16 in bone homeostasis, we created transgenic (TG) mice overexpressing human WNT16 in osteocytes using Dmp1 promoter (Dmp1-hWNT16 TG) on C57BL/6 (B6) background. We analyzed bone phenotypes and serum bone biomarkers, performed gene expression analysis and measured dynamic bone histomorphometry in Dmp1-hWNT16 TG and wild-type (WT) mice. Compared to WT mice, Dmp1-hWNT16 TG mice exhibited significantly higher whole-body, spine and femoral aBMD, BMC and trabecular (BV/TV, Tb.N, and Tb.Th) and cortical (bone area and thickness) parameters in both male and female at 12 weeks of age. Femur stiffness and ultimate force were also significantly improved in the Dmp1-hWNT16 TG female mice, compared to sex-matched WT littermates. In addition, female Dmp1-hWNT16 TG mice displayed significantly higher MS/BS, MAR and BFR/BS compared to the WT mice. Gene expression analysis demonstrated significantly higher mRNA level of Alp in both male and female Dmp1-hWNT16 TG mice and significantly higher levels of Osteocalcin, Opg and Rankl in the male Dmp1-hWNT16 TG mice in bone tissue compared to sex-matched WT mice. These results indicate that WNT16 plays a critical role for acquisition of both cortical and trabecular bone mass and strength. Strategies designed to use WNT16 as a target for therapeutic interventions will be valuable to treat osteoporosis and other low bone mass conditions.
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Acknowledgements
This work was supported by the US National Institutes of Health Grants AG041517 and AR053237, and Veteran’s Administration Grant BX001478.
Authors’ Contribution
IA and MJE designed the study. IA, AMR, MA, RLG, CK, DKO, WBW, DA, AKM, BP, KL, AGR and MJE conducted the study. IA, AMR, MA, RLG, CK, DKO, WBW, DA, AKM, BP, AMR, KL and AGR analyzed the data. IA, AMR, MA, RLG, AGR and MJE performed the data interpretation. IA, AGR and MJE are involved in drafting the manuscript. IA, AGR and MJE revised the manuscript content. IA, AMR, MA, RLG, CK, DKO, WBW, DA, AKM, BP, KL, AGR and MJE approved the final version of manuscript.
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Imranul Alam, Austin M. Reilly, Mohammed Alkhouli, Rita L. Gerard-O’Riley, Charishma Kasipathi, Dana K. Oakes, Weston B. Wright, Dena Acton, Amie K. McQueen, Bhavmik Patel, Kyung-Eun Lim, Alexander G. Robling and Michael J. Econs declare that they have no conflict of interest.
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Animal studies were performed in accordance with the ethical standards and guidelines approved by the Indiana University Animal Care and Use committee (IACUC). This article does not contain any studies with human participants performed by any of the authors.
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223_2016_225_MOESM1_ESM.tif
Supplemental Fig. 1. Osteoblast and osteoclast cellular parameters. Dmp1-hWNT16 transgenic female mice displayed similar values for N.Ob (1A), Ob.Pm (1B), N.Ob/B.Pm (1C) and Ob.S/BS (1C) compared to sex-matched WT mice. In addition, N.Oc (1A), Oc.Pm (1B), N.Oc/B.Pm (1D) and Oc.S/BS (1D) did not differ between Dmp1-hWNT16 transgenic female mice compared to the WT littermates. WT: wild-type; TG: Dmp1-hWNT16 transgenic (TIFF 695 kb)
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Alam, I., Reilly, A.M., Alkhouli, M. et al. Bone Mass and Strength are Significantly Improved in Mice Overexpressing Human WNT16 in Osteocytes. Calcif Tissue Int 100, 361–373 (2017). https://doi.org/10.1007/s00223-016-0225-4
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DOI: https://doi.org/10.1007/s00223-016-0225-4