ArticleJCI insight2024
Sclerostin blockade inhibits bone resorption through PDGF receptor signaling in osteoblast lineage cells.
Article in JCI insight, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Mechanisms underlying the waning of osteoanabolic therapy effects in osteoporosis.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2026Review
- Osteocytes in the Metastatic Bone Niche: Mechanistic Pathways and Therapeutic Targets.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Induced membrane-mediated DBM in combination with PRP: an autologous bone graft substitute therapy with remarkable osteoformation potency for challenging bone defects.International journal of surgery (London, England) · 2026Article
- Anabolic effects of Sost deficiency partially offset Opg deficiency-induced catabolism in cortical bone.Journal of bone and mineral metabolism · 2025Article
- The Interplay of Angiogenesis and Osteogenesis in Non-Stabilized Incomplete Tibial Fractures: A Temporal Study in Rats.Journal of orthopaedic research : official publication of the Orthopaedic Research Society · 2025Article
- PDGFR signalling implicated in anti-resorptive effects of sclerostin blockade.Nature reviews. Rheumatology · 2024Article
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.