ArticleImmunoTargets and therapy2025
Fracture-Induced Immunological Cascades Trigger Rapid Systemic Bone Loss via Osteocyte-Regulated Osteoclastogenesis.
Article in ImmunoTargets and therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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7 authors.
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Abstract
Background: Rapid bone loss after fracture elevates the risk of subsequent fractures, but the mechanisms remain unclear. IL-6, a key cytokine involved in fracture healing, is markedly upregulated during the immune response after fracture; however, its role in systemic skeletal deterioration remains poorly defined. Methods: In this study, we employed label-free proteomics to identify candidate mediators in vertebral samples following fracture. Next, osteocyte siRNA knockdown and Stattic (STAT3 phosphorylation inhibitor) inhibition were used to investigate IL-6 related signaling pathways. Subsequently, indirect co-cultures of osteocyte with osteoclast or osteoblast were used to evaluate the effects of the IL-6 pathway on bone resorption and formation. Furthermore, fractured mice were treated with MR16-1 (monoclonal anti-mouse IL-6 receptor antibody) or Stattic. Then, trabecular and cortical bone in vertebrae and femur were evaluated at 4, 14, and 28 days post-fracture, including histological analysis of p-STAT3 Results : In vitro, IL-6 dose-dependently elevated RANKL and p-STAT3 levels in osteocyte and promoted osteoclast activity in co-culture. These effects were suppressed by Stattic and replicated by STAT3 knockdown. In contrast, co-culture of osteocyte with osteoblast exhibited no significant alterations in osteogenic marker expression upon IL-6 exposure, suggesting negligible effects on osteoblast activity. In vivo, MR16-1 reduced trabecular bone loss in the vertebrae and femur after fracture. It also diminished p-STAT3 Conclusion: This study demonstrates that IL-6 drives osteoclast-mediated bone resorption via STAT3-dependent RANKL induction in osteocyte, thereby aggravating post-fracture systemic bone loss. And the findings highlight that modulating the IL-6/STAT3/RANKL axis and targeting osteocyte function may offer a promising therapeutic approach for preventing bone loss and minimizing the risk of fracture recurrence.
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