Xueping Li

Knee osteoarthritis (OA) is a leading cause of chronic pain and disability, yet the mechanisms linking central neuroinflammation to pain persistence remain poorly defined. This study identifies a novel perineuronal net (PNN)–microglia axis within the medial prefrontal cortex (mPFC) as a critical regulator of OA pain sensitization. Using a rat OA model, we demonstrate that high-intensity interval training (HIIT) exerts robust analgesic and disease-modifying effects, improving gait, reducing pain, and preserving cartilage integrity. HIIT markedly decreased PNN accumulation in the mPFC, driving microglial polarization away from a pro-inflammatory iNOS⁺ phenotype toward an anti-inflammatory Arg1⁺ phenotype, thereby mitigating central neuroinflammation. Importantly, pharmacological and enzymatic interventions confirmed that PNN remodeling precedes microglial phenotype switching, establishing a causal hierarchy in central inflammatory reprogramming. Parallel reductions in pro-inflammatory cytokines (IL-1β, TNF-α) and increases in IL-10 in both serum and synovial fluid underscore a systemic anti-inflammatory effect. Together, these findings reveal a previously unrecognized mechanism whereby exercise alleviates chronic pain by targeting central neuroimmune interactions, positioning HIIT as a promising non-pharmacological strategy for OA pain management through PNN-driven microglial modulation.

Osteoarthritis (OA) is associated with inflammatory responses linked to microglial polarisation within the central nervous system. However, exploring therapeutic approaches and their underlying mechanisms remains a direction for future research. The present study investigates the potential of high‐intensity interval training (HIIT) to alleviate inflammation and facilitate the shift from M1 to M2 microglial polarisation via the Jak2/Stat3 pathway in an OA rat model. Wistar rats were induced with OA via intra‐articular injection of monosodium iodoacetate and subsequently underwent HIIT for six consecutive weeks after a 4‐week establishment period. Pain thresholds were measured using the von Frey test. Immunofluorescence detected Tmem119, SP, Glu, c‐Fos, and IL‐6, while flow cytometry analysed CD68 and CD163 levels. Proteomics compared the protein differences between the OA and HIIT groups. The Jak2/Stat3 pathway was activated in OA rats with C‐A1 injections, followed by HIIT and subsequent Western blot analysis of inflammatory cytokines. The results indicated a significant decrease in pain threshold from the third to the tenth week in OA rats, while HIIT was found to increase pain thresholds. HIIT was found to promote M1 to M2 microglial polarisation and downregulate the expression of Tmem119, SP, Glu, c‐Fos, and IL‐6. Additionally, HIIT was more effective in suppressing Jak2 and Stat3 expression levels compared to OA rats. Activation of the Jak2/Stat3 pathway significantly increased the expression of Glu, c‐fos, SP, and IL‐6, but HIIT reversed these OA‐induced increases. Compared to the OA + C‐A1 group, the expression levels of Glu, c‐fos, SP, and IL‐6 were significantly reduced in the OA + C‐A1 + HIIT group. In conclusion, HIIT effectively mitigates OA‐induced inflammatory responses by reversing microglial polarisation through the Jak2/Stat3 pathway.

Objective: Osteoarthritis (OA)-induced neuropathic pain is closely related to microglial polarization in the central nervous system. This study aimed to determine whether high-intensity interval training (HIIT) could relieve neuropathic pain and promote the polarization of M1 to M2 in microglia through the Jak2/Stat3 pathway in OA rats. Methods: Wistar rats received intra-articular injection of monosodium iodoacetate for an OA model. After four weeks, moderate-intensity continuous training (MICT) or HIIT was conducted consecutively for six weeks. Pain threshold was measured by the von Frey test. The degree of cartilage damage was analyzed by magnetic resonance imaging and safranin-O staining. Tmem119, substance P (SP), Vglut2, c-Fos, and IL6 were detected by immunofluorescence. The CD68 and CD163 were analyzed by flow cytometry. The proteomics sequencing and quantitative real-time polymerase chain reaction analyzed the differences in protein and mRNA expression levels between MICT and HIIT groups. Intraperitoneal injection of C-A1 activated the Jak2/Stat3 pathway in OA rats, followed by HIIT treatment, and pain neurotransmitters were detected by Western blotting. Results: The pain threshold was significantly decreased from third weeks to tenth weeks in OA rats. HIIT treatment promoted the polarization of M1 to M2 in microglia and down-regulated Tmem119, SP, Vglut2, c-Fos, and IL6. Moreover, HIIT suppressed Jak2 and Stat3 expression levels when compared with MICT rats. The pain threshold and pain neurotransmitters were lower in C-A1+HIIT rats than in C-A1 rats. Conclusions: HIIT relieves OA-induced neuropathic pain and promotes the polarization of M1 to M2 in microglia through the Jak2/Stat3 pathway.

Background: Knee osteoarthritis (KOA) is the leading cause of pain and stiffness, affecting older adults’ physical function and quality of life. As a form of mind-body exercise, Tai Chi has been recommended as an exercise prescription for KOA patients. This study examined the effects and continuation of modified Tai Chi exercises on physical function and quality of life in elderly women with KOA.Methods: We conducted a single-blind, randomized controlled trial (RCT) on 40 older women with KOA. The participants were randomized to a 12 weeks Tai Chi or control group. The Tai Chi group attended a kind of modified Tai Chi training sessions three times per week; the control group attended wellness education sessions once a week. The primary outcome was the Western Ontario and McMaster University Osteoarthritis Index (WOMAC). Secondary outcomes were the Berg Balance Scale (BBS), Timed Up and Go (TUG), Short-Form 36 (SF-36), Pittsburgh Sleep Quality of Index (PSQI), Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS).Results: After the 12-weeks the Tai Chi group showed significan improvement in the WOMAC pain (mean difference, −5.09 points, p = 0.001), WOMAC stiffness (mean difference, −3.60 points, p = 0.002), WOMAC physical function (mean difference, −11.21 points, p = 0.001) compared to the control group. In addition, the Tai Chi group had also significant improvement in the BBS (mean difference, 1.70 points, p = 0.008), TUG (mean difference, −0.52s, p = 0.001), SF-36PCS (mean difference, 7.60 points, p = 0.001), MCS (mean difference, 7.30 points, p = 0.001), PSQI (mean difference, −3.71 points, p = 0.001), SDS (mean difference, −5.37 points, p = 0.025) and SAS (mean difference, −5.06 points, p = 0.002).Conclusion: The modified Tai Chi exercises are an effective treatment for improved physical function and quality of life in elderly women with KOA.Clinical Trial Registration: The trial was registered in Chinese Clinical Trial Registry (ChiCTR2000040721), http://www.chictr.org.cn/edit.aspx?pid=65419&htm=4.