BoneKEy Reports | BoneKEy Watch

PPARβ/δ and its role in Wnt signaling and bone turnover


An in silico analysis of the promoter regions of genes known to be involved in Wnt signaling revealed several elements in the gene coding for LRP5, a Wnt co-receptor, that responded to peroxisome proliferator-activated receptors (PPARs). Using chromatin immunoprecipitation, Scholtysek et al. showed that PPARβ/δ bound the LRP5 promoter in osteoblastic MC3T3 cells. Further experiments confirmed that PPARβ/δ was indeed interacting with Lrp5 and was amplifying both Wnt signaling and β-catenin signaling.

Activating PPARβ/δ led to osteogenic differentiation of osteoblasts, and an agonist of PPARβ/δ induced osteoprotegerin (OPG) expression and reduced the RANKL:OPG ratio. Osteoclast differentiation and bone resorption were both inhibited as a result.

Mice with a conditional deletion of the gene encoding PPARδ developed osteopenia in their vertebral and long bones and showed greater numbers of osteoclasts in their trabecular bones. They also showed reduced Wnt signaling and lower serum levels of OPG. Activating PPARβ/δ in a murine model of postmenopausal osteoporosis rebalanced bone turnover, returning bone density to normal levels.

Editor’s comment: We already knew about the prominent role of PPARγ on the regulation of osteoblastic and osteoclastic functions. Using an original transgenic approach to circumvent the embryonic mortality of PPAR allele deletion, this study now demonstrates that PPARβ/δ, the predominant PPAR in skeletal muscle, is also expressed in osteoblasts, where it indirectly inhibits bone resorption. Although the role of this pathway on bone formation in vivo needs to be clarified, this work provides further molecular and pharmacological insights into the modulation of bone turnover.

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