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• W4386770156 abstract "Abstract While sclerostin-neutralizing antibodies (Scl-Ab) transiently stimulate bone formation by activating Wnt signaling in osteoblast lineage cells, they exert sustained inhibition of bone resorption, suggesting an alternate signaling pathway by which Scl-Ab control osteoclast activity. Since sclerostin can activate platelet-derived growth factor receptors (PDGFRs) in osteoblast lineage cells in vitro and PDGFR signaling in these cells induces bone resorption through M-CSF secretion, we hypothesized that the prolonged anti-catabolic effect of Scl-Ab could result from PDGFR inhibition. We show here that inhibition of PDGFR signaling in osteoblast lineage cells is sufficient and necessary to mediate prolonged Scl-Ab effect on Csf1 expression (encoding M-CSF) and osteoclast activity in mice. Indeed, sclerostin co-activates PDGFRs independently of Wnt/β-catenin signaling inhibition, by forming a ternary complex with LRP6 and PDGFRs. In turn, Scl-Ab prevents sclerostin-mediated co-activation of PDGFR signaling and consequent Csf1 up-regulation in osteoblast cultures, thereby inhibiting bone resorption in osteoblasts/osteoclasts co-cultures. These results provide a new potential mechanism explaining the lack of counter-regulation of Scl-Ab effect on bone resorption." @default.
• W4386770156 created "2023-09-16" @default.
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• W4386770156 date "2023-09-15" @default.
• W4386770156 modified "2023-09-26" @default.
• W4386770156 title "Sclerostin blockade inhibits bone resorption through PDGF receptor signaling in osteoblast lineage cells" @default.
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• W4386770156 doi "https://doi.org/10.1101/2023.09.11.557168" @default.
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