2. Academic Validation
  3. S-propargyl-cysteine attenuates temporomandibular joint osteoarthritis by regulating macrophage polarization via Inhibition of JAK/STAT signaling

S-propargyl-cysteine attenuates temporomandibular joint osteoarthritis by regulating macrophage polarization via Inhibition of JAK/STAT signaling

  • Mol Med. 2025 Apr 7;31(1):128. doi: 10.1186/s10020-025-01186-6.
Wenyi Cai # 1,  Antong Wu # 1 2,  Zhongxiao Lin # 3 4,  Wei Cao 1,  Janak L Pathak 1,  Richard T Jaspers 1 2,  Rui Li 1,  Xin Li 1,  Kaihan Zheng 1,  Yufu Lin 1,  Na Zhou 3,  Xin Zhang 3,  Yizhun Zhu 5,  Qingbin Zhang 6
Affiliations

Affiliations

  • 1 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.
  • 2 Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Science, Amsterdam, The Netherlands.
  • 3 School of Pharmacy, State Key Laboratory of Quality Research in Chinese Medicines and Laboratory of Drug Discovery from Natural Resources and Industrialization, Macau University of Science and Technology, Room 210, Block E, Avenida Wai Long, Taipa, Macau, China.
  • 4 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
  • 5 School of Pharmacy, State Key Laboratory of Quality Research in Chinese Medicines and Laboratory of Drug Discovery from Natural Resources and Industrialization, Macau University of Science and Technology, Room 210, Block E, Avenida Wai Long, Taipa, Macau, China. yzzhu@must.edu.mo.
  • 6 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. qingbinzhang@gzhmu.edu.cn.
  • # Contributed equally.
PMID: 40197110 DOI: 10.1186/s10020-025-01186-6
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Hydrogen sulfide; JAK/STAT; Macrophage; S-propargyl-cysteine; Synovial; Temporomandibular joint osteoarthritis.

Figures
Products