Zhang Yuxin, Zhang Dahe, Xu Qingyu, Xia Simo, Shen Pei, Yang Chi
Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai 200011, China; Shanghai Key Laboratory of Orthopedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai 200011, China.
Int Immunopharmacol. 2025 Feb 6;147:113996. doi: 10.1016/j.intimp.2024.113996. Epub 2025 Jan 4.
Temporomandibular joint osteoarthritis (TMJ OA) is a common degenerative disease characterized by cartilage degeneration. However, the therapeutic strategies aimed to maintain cartilage homeostasis remain unclear. Fostamatinib (Fos) is a potential clinical drug for rheumatoid arthritis (RA) and predicted as target drug for many inflammatory diseases. In this study we investigated the therapeutic effects of Fos for TMJ OA and underlying mechanisms. Interleukin-1β (IL-1β) was used to construct a condylar chondrocyte injury model in vitro and rat TMJ OA models were induced by unilateral anterior crossbite (UAC) in vivo. Subsequently, a series of experiments were performed to assess the therapeutic effects and potential mechanisms of Fos in TMJ OA. Herein, we verified that Fos improved IL-1β-induced decrease in chondrocyte viability and proliferation, as well as inhibited cell apoptosis. Additionally, Fos could alleviate IL-1β-induced inflammation, ECM degradation, and chondrocyte phenotype change through blocking MAPK/NF-κB pathways, as well as promote chondrocyte autophagy by regulating AKT/mTOR pathways. The therapeutic effects of Fos on TMJ OA were further validated through rat UAC model in vivo. Overall, Fos could maintaining cartilage homeostasis through regulating chondrocyte inflammation, ECM degradation, and abnormal cell biological behaviors (apoptosis and autophagy), which made it a promising small molecule drug for TMJ OA early intervention.
颞下颌关节骨关节炎（TMJ OA）是一种以软骨退变为特征的常见退行性疾病。然而，旨在维持软骨内环境稳定的治疗策略仍不明确。 fostamatinib（Fos）是一种治疗类风湿性关节炎（RA）的潜在临床药物，并被预测为许多炎症性疾病的靶向药物。在本研究中，我们研究了Fos对TMJ OA的治疗作用及其潜在机制。在体外，使用白细胞介素-1β（IL-1β）构建髁突软骨细胞损伤模型，在体内通过单侧前牙反合（UAC）诱导大鼠TMJ OA模型。随后，进行了一系列实验以评估Fos在TMJ OA中的治疗作用和潜在机制。在此，我们证实Fos改善了IL-1β诱导的软骨细胞活力和增殖的降低，并抑制了细胞凋亡。此外，Fos可通过阻断MAPK/NF-κB信号通路减轻IL-1β诱导的炎症、细胞外基质降解和软骨细胞表型改变，并通过调节AKT/mTOR信号通路促进软骨细胞自噬。Fos对TMJ OA 的治疗作用在大鼠UAC体内模型中得到进一步验证。总体而言，Fos可通过调节软骨细胞炎症、细胞外基质降解和异常细胞生物学行为（凋亡和自噬）来维持软骨内环境稳定，这使其成为一种有前景的用于TMJ OA早期干预 的小分子药物。
