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. 2025 Aug 2:18:10403-10423.
doi: 10.2147/JIR.S535311. eCollection 2025.

Chinese Massage (Tuina) Attenuates Knee Osteoarthritis by Modulating Autophagy-Related Cytokines: A Multidisciplinary Methodological Investigation

Zhen Wang #  1 , Chi Zhao #  1   2 , Mengmeng Li #  1   2 , Lili Zhang #  1 , Jieyao Diao  1 , Yiming Wu  2 , Tao Yang  2 , Mingwei Shi  2 , Yang Lei  2 , Yu Wang  3 , Miaoxiu Li  4 , Yanqin Bian  5 , Yunfeng Zhou  1 , Hui Xu  1   2
Affiliations

Chinese Massage (Tuina) Attenuates Knee Osteoarthritis by Modulating Autophagy-Related Cytokines: A Multidisciplinary Methodological Investigation

Zhen Wang et al. J Inflamm Res. .

Abstract

Background: Tuina therapy has demonstrated its potential in modulating autophagy-related factors in knee osteoarthritis (KOA); however, its core therapeutic targets and specific mechanisms require systematic elucidation through interdisciplinary research.

Objective: This study investigated the mechanism by which Tuina alleviates KOA progression using multidimensional approaches, including Mendelian randomization (MR), in vivo experiments, and machine learning.

Methods: Genetic data from genome-wide association studies of 60 cytokines and KOA were analyzed using MR analysis to identify autophagy-related factors significantly associated with KOA. A KOA rat model was established via intra-articular injections of L-cysteine-activated papain solution into the right knee. The key autophagy-related cytokines identified by MR were validated using enzyme-linked immunosorbent assay (ELISA). Cartilage degeneration and autophagic activity were assessed through histological evaluation via safranin O/fast green (SO/FG) staining and ultrastructural analysis via transmission electron microscopy (TEM). A Support Vector Machine (SVM) algorithm was used to conduct a secondary analysis of the experimental dataset to predict comprehensive therapeutic effects and synergistic correlations among the indicators.

Results: MR analysis revealed causal relationships between eight cytokines and KOA at genetically determined levels, with seven exhibiting autophagy-related regulatory properties. Tuina significantly alleviated pain and improved motor function. SO/FG staining and TEM revealed reduced cartilage destruction, increased cartilage thickness, and decreased chondrocyte autophagy. ELISA revealed that Tuina downregulated interferon gamma, parathyroid hormone, interleukin (IL)-1β, matrix metalloproteinase-3, and IL-17 levels in the cartilage while upregulating osteocalcin and transforming growth factor-β1 levels. Furthermore, Tuina demonstrated superior comprehensive and classified curative effects compared with celecoxib. IFN-γ and PTH were strongly correlated with both relative autophagy level and cartilage area ratio. Autophagy-related cytokines had the strongest correlation with the degree of cartilage degeneration.

Conclusion: Tuina therapy alleviates pain and functional impairment in KOA by suppressing chondrocyte autophagy and delaying cartilage degeneration. This mechanism may involve the regulation of autophagy-related cytokines.

Keywords: Mendelian randomization; Tuina; autophagy-related cytokines; in vivo experiment; knee osteoarthritis; machine learning.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Overview technical route of the study design.
Figure 2
Figure 2
The summary results of the MR Analysis.
Figure 3
Figure 3
The forest plot of the eight causal relationships identified by the MR Analysis.
Figure 4
Figure 4
Effect of Tuina on behavioral indicators of the knee joint in KOA rats.
Figure 5
Figure 5
(A) Observation results of SO/FG stained knee cartilage of rats in each group under light microscope. Scale, 200µm. (B) Cartilage area ratio in each group.
Figure 6
Figure 6
Observation results of knee cartilage of rats in each group under under 8000x (A) and 3000x (B) TEM. (C) relative autophagy level in each group.
Figure 7
Figure 7
Effects of Tuina on the Levels of Autophagy-related Cytokines in Knee Cartilage Tissues of KOA Rats.
Figure 8
Figure 8
Confusion matrix diagram for model performance.
Figure 9
Figure 9
Individual correlation analysis in the SVM model.
Figure 10
Figure 10
Categorical correlation analysis in the SVM model.
Figure 11
Figure 11
Confusion matrix diagram for curative effect analysis.
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