Abstract
Peroxisome proliferator-activated receptors (PPARs) act as metabolic sensors and central regulators of fat and glucose homeostasis1. Furthermore, PPARγ has been implicated as major catabolic regulator of bone mass in mice and humans2,3,4,5. However, a potential involvement of other PPAR subtypes in the regulation of bone homeostasis has remained elusive. Here we report a previously unrecognized role of PPARβ/δ as a key regulator of bone turnover and the crosstalk between osteoblasts and osteoclasts. In contrast to activation of PPARγ, activation of PPARβ/δ amplified Wnt-dependent and β-catenin–dependent signaling and gene expression in osteoblasts, resulting in increased expression of osteoprotegerin (OPG) and attenuation of osteoblast-mediated osteoclastogenesis. Accordingly, PPARβ/δ-deficient mice had lower Wnt signaling activity, lower serum concentrations of OPG, higher numbers of osteoclasts and osteopenia. Pharmacological activation of PPARβ/δ in a mouse model of postmenopausal osteoporosis led to normalization of the altered ratio of tumor necrosis factor superfamily, member 11 (RANKL, also called TNFSF11) to OPG, a rebalancing of bone turnover and the restoration of normal bone density. Our findings identify PPARβ/δ as a promising target for an alternative approach in the treatment of osteoporosis and related diseases.
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Acknowledgements
We thank M. Steffen, U. Hillienhoff and I. Schmidt for technical assistance and J. Wittmann for his help during the analysis of the Lrp5 promoter. Wnt3a-expressing L cells were kindly provided by K. Tanneberger (Department of Experimental Medicine II, University of Erlangen). This study was supported by the Deutsche Forschungsgemeinschaft (KR3523, FG 661, SFB643 and SPP1468-IMMUNOBONE), the Bundesministerium für Bildung und Forschung (BMBF; project ANCYLOSS); the ELAN Program of the University of Erlangen-Nuremberg; the MASTERSWITCH and IMI projects of the European Union; the Interdisciplinary Centre for Clinical Research (IZKF) Erlangen; and the Bayrische Forschungsstftung.
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C. Scholtysek planned and performed in vitro and in vivo experiments, conducted data analyses and wrote the manuscript. J.K., H.F., S.U. and M.M.Z. conducted data analyses and performed in vivo and in vitro experiments. N.I. and F.D. performed MSC differentiation and characterization and conducted the related experiments and data analyses. C. Stoll cloned and characterized the Lrp5 promoter. M.S., L.D., C.B. and A.K. performed histological data acquisition and data analyses. A.H., K.E. and J.P.T. established, performed and interpreted the microcomputer tomography–based bone analyses. B.D. generated and provided PpardSox2-cKO mice and contributed to the study design. J.-P.D. and G.S. provided input and wrote the manuscript. G.K. supervised the project, planned and conducted experiments and data analysis and wrote the manuscript.
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Scholtysek, C., Katzenbeisser, J., Fu, H. et al. PPARβ/δ governs Wnt signaling and bone turnover. Nat Med 19, 608–613 (2013). https://doi.org/10.1038/nm.3146
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DOI: https://doi.org/10.1038/nm.3146
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