ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1659230
SHP2 Inhibition by SHP099 Attenuates IL-6-Driven Osteoclastogenesis in Growth Plate Injury
Provisionally accepted
- 1Shanghai Jiaotong University School of Medicine Xinhua Hospital, Shanghai, China
- 2The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- 3Children's Hospital of Shanghai, Shanghai, China
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Disruption of growth plate cartilage often leads to serious bone growth defects in children and adolescents, necessitating effective therapeutic strategies to enhance bone repair. This study investigates the role of SHP2, a protein expressed in osteocytes, in regulating osteoclastogenesis and bone remodeling in the context of growth plate injuries. Following growth plate injury, an inflammatory response is rapidly initiated, resulting in the release of pro-inflammatory cytokines such as IL-6 into the injured tissue, which subsequently induce and enhance osteoclast generation and differentiation. Utilizing a tibial growth plate drill-hole injury model in C57BL/6 mice, we demonstrated that SHP2 is upregulated at the injury site, where it mediates the effects of IL-6. Intraarticular administration of the SHP2 inhibitor SHP099 significantly reduced osteoclast numbers and decreased the expression of osteoclast markers (cathepsin K and OSCAR), as well as pro-inflammatory cytokines (IL-6, IL-1β, TNFα) in the injured tissue. In vitro studies with RAW 264.7 cells confirmed that IL-6 enhances SHP2 and TAK1 expression, promoting osteoclast differentiation, an effect that was effectively inhibited by SHP099. Furthermore, the NF-κB pathway remained unaffected by SHP099, indicating a distinct signaling mechanism through which SHP2 regulates osteoclastogenesis.Our findings underscore the pivotal role of SHP2 as a downstream signaling molecule of IL-6 in mediating inflammatory responses during bone repair, suggesting that SHP2 inhibition may present a novel therapeutic approach to prevent pathological bone remodeling and enhance recovery following growth plate injuries. Future investigations should focus on the translational potential of SHP2 inhibitors in pediatric orthopedics.
Keywords: SHP2, SHP099, IL-6, Osteoclasts, Growth plate injury
Received: 03 Jul 2025; Accepted: 24 Jul 2025.
Copyright: © 2025 Zhang, Li, Dai, Liu, Sha and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Qin Zhang, Shanghai Jiaotong University School of Medicine Xinhua Hospital, Shanghai, China
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