Department of Orthopaedics, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.
Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
J Cell Mol Med. 2021 Aug;25(16):7709-7719. doi: 10.1111/jcmm.16617. Epub 2021 Jun 29.
Traumatic heterotopic ossification (HO) is the abnormal formation of bone in soft tissues as a consequence of injury. However, the pathological mechanisms leading to traumatic HO remain unknown. Here, we report that aberrant expression of IL-17 promotes traumatic HO formation by activating β-catenin signalling in mouse model. We found that elevated IL-17 and β-catenin levels are correlated with a high degree of HO formation in specimens from patients and HO animals. We also show that IL-17 initiates and promotes HO progression in mice. Local injection of an IL-17 neutralizing antibody attenuates ectopic bone formation in a traumatic mouse model. IL-17 enhances the osteoblastic differentiation of mesenchymal stem cells (MSCs) by activating β-catenin signalling. Moreover, inhibition of IL-17R or β-catenin signalling by neutralizing antibodies or drugs prevents the osteogenic differentiation of isolated MSCs and decreases HO formation in mouse models. Together, our study identifies a novel role for active IL-17 as the inducer and promoter of ectopic bone formation and suggests that IL-17 inhibition might be a potential therapeutic target in traumatic HO.
创伤性异位骨化（HO）是由于损伤导致骨在软组织中异常形成。然而，导致创伤性 HO 的病理机制尚不清楚。在这里，我们报告异常表达的白细胞介素-17（IL-17）通过激活β-连环蛋白信号通路促进小鼠模型中创伤性 HO 的形成。我们发现，在患者和 HO 动物的标本中，升高的 IL-17 和 β-连环蛋白水平与 HO 形成的高度相关。我们还表明，IL-17 在小鼠中启动并促进 HO 的进展。局部注射白细胞介素-17 中和抗体可减轻创伤性小鼠模型中的异位骨形成。IL-17 通过激活β-连环蛋白信号通路增强间充质干细胞（MSCs）的成骨分化。此外，通过中和抗体或药物抑制 IL-17R 或β-连环蛋白信号通路可防止分离的 MSCs 的成骨分化，并减少小鼠模型中的 HO 形成。总之，我们的研究确定了活跃的白细胞介素-17 作为异位骨形成的诱导剂和促进剂的新作用，并表明白细胞介素-17 抑制可能是创伤性 HO 的潜在治疗靶点。
