PPAR  regulates bone-metabolism by facilitating Wnt-signalling

Background Peroxisome proliferator-activated receptors (PPARs) act as key factors during the regulation of fat and glucose metabolism. In addition, the PPAR[GAMMA] isoform has been implicated as major catabolic regulator of bone homeostasis in mice and humans. Materials and methods By using PPARβ-specific agonists and PPARβ-deficient mice, the authors analysed the role of PPARβ in osteoblasts and bone homeostasis in vitro and in vivo. Results Here the authors describe a novel role of its family member PPARβ as anabolic regulator of bone. In contrast to PPAR[GAMMA], PPARβ acted in a permissive manner on Wnt-signalling in osteoblasts. Activation of PPARβ induced expression of the Wnt-co-receptor LRP5, promoted nuclear accumulation of β-catenin and consequently enhanced TCF-driven transcriptional activity. Thereby, PPARβ augmented expression of different Wnt-dependent genes, such as osterix and osteoprotegerin (opg ), in osteoblasts. Consequently, activation of PPARβ in osteoblasts blocked the differentiation of bone-resorbing osteoclasts. Mice deficient in PPARβ, displayed reduced Wnt-signalling activity and low serum levels of OPG associated with increased differentiation of osteoclasts and osteopenia. Conversely, pharmacological treatment with PPARβ-specific agonist blocked the formation of osteoclasts in vivo and protected mice from ovariectomy-induced bone loss. Conclusion These data reveal a so far unrecognised role of PPARβ in the crosstalk between energy metabolism and bone homeostasis and highlights its potential to serve as a target for the treatment of osteoporosis.