Sclerostin blockade inhibits bone resorption through PDGF receptor signaling in osteoblast lineage cells.
JCI Insight
; 9(10)2024 May 22.
Article
em En
| MEDLINE
| ID: mdl-38713511
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/ß-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.
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Base de dados:
MEDLINE
Assunto principal:
Osteoblastos
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Osteoclastos
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Reabsorção Óssea
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Transdução de Sinais
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Receptores do Fator de Crescimento Derivado de Plaquetas
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Proteínas Adaptadoras de Transdução de Sinal
Limite:
Animals
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article