Cai Wenyi, Wu Antong, Lin Zhongxiao, Cao Wei, Pathak Janak L, Jaspers Richard T, Li Rui, Li Xin, Zheng Kaihan, Lin Yufu, Zhou Na, Zhang Xin, Zhu Yizhun, Zhang Qingbin
Department of Temporomandibular Joint, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, 195 Dongfeng Road (West), Yuexiu District, Guangzhou, Guangdong, 510140, China.
Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Science, Amsterdam, The Netherlands.
Mol Med. 2025 Apr 7;31(1):128. doi: 10.1186/s10020-025-01186-6.
Temporomandibular joint osteoarthritis (TMJ-OA) is a disease characterized by cartilage degradation and synovial inflammation, with limited effective treatment currently. Synovial macrophage polarization is pivotal in TMJ-OA progression, making it a promising therapeutic aspect. This study investigated the effects of S-propargyl-cysteine (SPRC), an endogenous H2S donor, on macrophage polarization and its therapeutic potential in alleviating TMJ-OA.
A MIA-induced TMJ-OA rat model and LPS-stimulated RAW264.7 macrophages were employed to evaluate the effects of SPRC in vivo and in vitro. TMJ bone and cartilage were analyzed via micro-CT and histological methods, while macrophage polarization markers expression were assessed via RT-qPCR, western blot, and immunofluorescence. RNA sequencing was performed on macrophages, and the JAK2/STAT3 signaling pathway was validated using the JAK2-specific inhibitor AG490. The direct effects of SPRC on rat primary condylar chondrocytes were examined by evaluating ECM synthesis and degradation. Co-culture experiments further assessed macrophage-chondrocyte interactions.
SPRC significantly alleviated cartilage and bone damage in the TMJ-OA rat model, as demonstrated by improved bone volume and cartilage structure. SPRC reduced pro-inflammatory M1 macrophage infiltration and enhanced anti-inflammatory M2 macrophage polarization. SPRC effectively inhibited the JAK2/STAT3, leading to reduction of inflammatory markers, including TNF-α, IL-6, and iNOS. Co-culture experiments revealed that SPRC-treated macrophage-conditioned medium improved chondrocyte metabolic activity and restored ECM integrity.
SPRC-modulated macrophage polarization alleviates TMJ-OA via JAK/STAT downregulation, thereby reducing synovial inflammation and cartilage degradation. These findings position SPRC as a promising therapeutic candidate for TMJ-OA and provide insights into novel strategies targeting macrophage polarization and synovium-cartilage crosstalk.
颞下颌关节骨关节炎（TMJ - OA）是一种以软骨降解和滑膜炎症为特征的疾病，目前有效治疗方法有限。滑膜巨噬细胞极化在TMJ - OA进展中起关键作用，使其成为一个有前景的治疗方向。本研究调查了内源性硫化氢供体S - 炔丙基 - 半胱氨酸（SPRC）对巨噬细胞极化的影响及其在缓解TMJ - OA中的治疗潜力。
采用MIA诱导的TMJ - OA大鼠模型和LPS刺激的RAW264.7巨噬细胞来评估SPRC在体内和体外的作用。通过显微CT和组织学方法分析TMJ的骨和软骨，同时通过RT - qPCR、western blot和免疫荧光评估巨噬细胞极化标志物的表达。对巨噬细胞进行RNA测序，并使用JAK2特异性抑制剂AG490验证JAK2/STAT3信号通路。通过评估细胞外基质（ECM）的合成和降解来检测SPRC对大鼠原代髁突软骨细胞的直接作用。共培养实验进一步评估巨噬细胞与软骨细胞的相互作用。
SPRC显著减轻了TMJ - OA大鼠模型中的软骨和骨损伤，骨体积和软骨结构得到改善证明了这一点。SPRC减少了促炎M1巨噬细胞浸润并增强了抗炎M2巨噬细胞极化。SPRC有效抑制JAK2/STAT3，导致包括TNF -α、IL - 6和诱导型一氧化氮合酶（iNOS）在内的炎症标志物减少。共培养实验表明，经SPRC处理的巨噬细胞条件培养基改善了软骨细胞的代谢活性并恢复了ECM完整性。
SPRC调节的巨噬细胞极化通过下调JAK/STAT减轻TMJ - OA，从而减少滑膜炎症和软骨降解。这些发现使SPRC成为TMJ - OA有前景的治疗候选药物，并为靶向巨噬细胞极化和滑膜 - 软骨相互作用的新策略提供了见解。
