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PPARβ/δ governs Wnt signaling and bone turnover

Scholtysek, Carina, Katzenbeisser, Julia, Fu, He, Uderhardt, Stefan, Ipseiz, Natacha, Stoll, Cornelia, Zaiss, Mario M, Stock, Michael, Donhauser, Laura, Böhm, Christina, Kleyer, Arnd, Hess, Andreas, Engelke, Klaus, David, Jean-Pierre, Djouad, Farida, Tuckermann, Jan Peter, Desvergne, Béatrice, Schett, Georg and Krönke, Gerhard 2013. PPARβ/δ governs Wnt signaling and bone turnover. Nature Medicine 19 (5) , pp. 608-613. 10.1038/nm.3146

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Abstract

Peroxisome proliferator-activated receptors (PPARs) act as metabolic sensors and central regulators of fat and glucose homeostasis. Furthermore, PPARγ has been implicated as major catabolic regulator of bone mass in mice and humans. 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. © 2013 Nature America, Inc. All rights reserved.

Item Type: Article
Schools: Medicine
Publisher: Nature Publishing Group
ISSN: 1078-8956
Last Modified: 19 Dec 2019 16:15
URI: http://orca-mwe.cf.ac.uk/id/eprint/127549

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