title: PPARβ/δ governs Wnt signaling and bone turnover.
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.
authors.affiliation: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Scholtysek
authors.forename: Julia
authors.initials: J
authors.lastname: Katzenbeisser
authors.forename: He
authors.initials: H
authors.lastname: Fu
authors.forename: Stefan
authors.initials: S
authors.lastname: Uderhardt
authors.forename: Natacha
authors.initials: N
authors.lastname: Ipseiz
authors.forename: Cornelia
authors.initials: C
authors.lastname: Stoll
authors.forename: Mario M
authors.initials: MM
authors.lastname: Zaiss
authors.forename: Michael
authors.initials: M
authors.lastname: Stock
authors.forename: Laura
authors.initials: L
authors.lastname: Donhauser
authors.forename: Christina
authors.initials: C
authors.lastname: Böhm
authors.forename: Arnd
authors.initials: A
authors.lastname: Kleyer
authors.forename: Andreas
authors.initials: A
authors.lastname: Hess
authors.forename: Klaus
authors.initials: K
authors.lastname: Engelke
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: David
authors.forename: Farida
authors.initials: F
authors.lastname: Djouad
authors.forename: Jan Peter
authors.initials: JP
authors.lastname: Tuckermann
authors.forename: Béatrice
authors.initials: B
authors.lastname: Desvergne
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Gerhard
authors.initials: G
authors.lastname: Krönke
mesh_terms: D000483:Alleles; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000378:metabolism; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology; D053244:Osteoprotegerin / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism*; D048068:PPAR-beta / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D053244:Osteoprotegerin; D047494:PPAR delta; D048068:PPAR-beta; D053245:RANK Ligand; C506031:Tnfrsf11b protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin; D005947:Glucose
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