Fostamatinib alleviates temporomandibular joint osteoarthritis by maintaining cartilage homeostasis through MAPK/NF-κB and AKT/mTOR pathways

Yuxin Zhang; Dahe Zhang; Qingyu Xu; Simo Xia; Pei Shen; Chi Yang

doi:10.1016/j.intimp.2024.113996

Fostamatinib alleviates temporomandibular joint osteoarthritis by maintaining cartilage homeostasis through MAPK/NF-κB and AKT/mTOR pathways

Int Immunopharmacol. 2025 Jan 4:147:113996. doi: 10.1016/j.intimp.2024.113996. Online ahead of print.

Authors

Yuxin Zhang¹, Dahe Zhang², Qingyu Xu², Simo Xia², Pei Shen³, Chi Yang⁴

Affiliations

¹ 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.
² 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.
³ 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. Electronic address: [email protected].
⁴ 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. Electronic address: [email protected].

PMID: 39756165
DOI: 10.1016/j.intimp.2024.113996

Abstract

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.

Keywords: AKT/mTOR pathways; Cartilage homeostasis; Chondrocyte; Fostamatinib; MAPK/NF-κB pathways; Temporomandibular joint osteoarthritis.