Sclerostin blockade inhibits bone resorption through PDGF receptor signaling in osteoblast lineage cells

Article Article scientifique Article Sclerostin blockade inhibits bone resorption through PDGF receptor signaling in osteoblast lineage cells eng 2024-05-22 2024-05-22 author Thouverey Cyril 689566 Département de médecine (DEMED) author Apostolides Pierre 23057 Département de médecine (DEMED) author Brun Julia 814292 author Caverzasio Joseph 22307 author Ferrari Serge Livio 24314 Département de médecine (DEMED) e176558 10.1172/jci.insight.176558 38713511 2379-3708 PMC11141910 https://insight.jci.org/articles/view/176558 While sclerostin-neutralizing antibodies (Scl-Abs) 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-Abs 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 anticatabolic effect of Scl-Abs 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 effects on M-CSF secretion and osteoclast activity in mice. Indeed, sclerostin coactivates PDGFRs independently of Wnt/β-catenin signaling inhibition, by forming a ternary complex with LRP6 and PDGFRs in preosteoblasts. In turn, Scl-Ab prevents sclerostin-mediated coactivation of PDGFR signaling and consequent M-CSF upregulation in preosteoblast cultures, thereby inhibiting osteoclast activity in preosteoblast/osteoclast coculture assays. These results provide a potential mechanism explaining the dissociation between anabolic and antiresorptive effects of long-term Scl-Ab. Bone biology Osteoclast/osteoblast biology Osteoporosis Signal transduction Animals Osteoblasts / metabolism Mice Adaptor Proteins, Signal Transducing / metabolism Bone Resorption / metabolism Signal Transduction Osteoclasts / metabolism Receptors, Platelet-Derived Growth Factor / metabolism Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors Wnt Signaling Pathway / drug effects Antibodies, Neutralizing / pharmacology Low Density Lipoprotein Receptor-Related Protein-6 / metabolism Macrophage Colony-Stimulating Factor / metabolism Cell Lineage Osteogenesis / drug effects Cell Differentiation Dewey 616 Swiss National Science Foundation Mechanisms of bone fragility and response to RANK Ligand and Sclerostin inhibitors 185230 CH Projects 56 Département de médecine 221 false 289 Métabolisme osseux 544 https://doi.org/10.5281/zenodo.7670092 JCI insight 9 10 e983a4db-911b-4418-a1de-213dac41858c Article (Published version) Public 176558.2-20240531124051-covered-e0f.pdf 7265047 application/pdf CC BY-4.0 faaeb6336e60a065d1710a0f4d95f71a91d22125bda931b31bc2d839827d3419 e82e1a62-02ff-4e10-958c-fa9fb7f57aa9 Supplemental data Public jci.insight.176558.sd.pdf 927325 application/pdf 3350eb1ac749732ce6e166c7c89419ca1bf5d3e220691257cae3551002f8d9f4 4250cba8-bc49-4fe0-8075-bc1a6c15feb4 Supplemental data Public jci.insight.176558.sdgels.pdf 1183769 application/pdf edc28b9883b84f74e62d34b6e2a2f47eec851ce8beca92250d7ea2dd2b77c23a 655a81e5-7545-4c1a-9ef9-7a2f8031d236 Supplemental data Public jci.insight.176558.sdval.xlsx 30770927 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet e8fa7876aefcf47e5edd8997553173b2988f7994f90b606ba84fe64757523438 Vignette Public jci.insight.176558.ga.jpg 202140 image/png openAccess Faculté de médecine / Section de médecine clinique / Département de médecine

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Sclerostin blockade inhibits bone resorption through PDGF receptor signaling in osteoblast lineage cells	JCI insight			2024	124	168

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Apostolides, Pierre