ResearchIn-Press PreviewBone biology Open Access | 10.1172/jci.insight.176558
1Service of Bone Diseases, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland
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1Service of Bone Diseases, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland
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1Service of Bone Diseases, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland
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1Service of Bone Diseases, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland
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1Service of Bone Diseases, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland
Find articles by Ferrari, S. in: JCI | PubMed | Google Scholar
Published May 7, 2024 - More info
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 M-CSF secretion 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 pre-osteoblasts. In turn, Scl-Ab prevents sclerostin-mediated co-activation of PDGFR signaling and consequent M-CSF up-regulation in pre-osteoblast cultures, thereby inhibiting osteoclast activity in pre-osteoblast/osteoclast co-culture assays. These results provide a new potential mechanism explaining the dissociation between anabolic and anti-resorptive effects of long-term Scl-Ab.