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Scientific article
Open access
English

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

Published inJCI insight, vol. 9, no. 10, e176558
Publication date2024-05-22
First online date2024-05-22
Abstract

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.

eng
Keywords
  • 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
Citation (ISO format)
THOUVEREY, Cyril et al. Sclerostin blockade inhibits bone resorption through PDGF receptor signaling in osteoblast lineage cells. In: JCI insight, 2024, vol. 9, n° 10, p. e176558. doi: 10.1172/jci.insight.176558
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Article (Published version)
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Identifiers
ISSN of the journal2379-3708
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