Electroacupuncture attenuates synovitis in knee osteoarthritis and is associated with modulation of the protein S-TAM (Axl/MerTK)-Rac1 signaling axis.

BACKGROUND

Synovitis, a core pathological feature of knee osteoarthritis (KOA), drives pain and disease progression via sustained inflammation and disrupted tissue homeostasis. Electroacupuncture (EA) shows clinical benefits in KOA management, yet its specific molecular mechanisms against synovitis remain incompletely defined. The Protein S-Tyro3, Axl, MerTK (TAM) pathway-particularly Axl/MerTK and downstream Rac1-constitutes a key efferocytosis-related and inflammation-resolving signaling axis. We hypothesized that EA alleviates KOA synovitis and is associated with restoration of this dysregulated pathway.

METHODS

Male Sprague-Dawley rats were randomly assigned to Control, KOA (anterior cruciate ligament transection, ACLT), and KOA-EA groups. After 1 month of model induction, the KOA-EA group received EA at GB34, SP10, ST36, and KI3 (30 min/day, 5 days/week for 12 weeks; sparse-dense waves: 3/15 Hz, 1 mA). We assessed cartilage histopathology (Mankin's/OARSI scores), synovitis (Krenn score), synovial apoptosis (TUNEL, Cleaved Caspase-3/F4/80 co-staining), serum cytokines (IL-1β, TNF-α, IL-10, TGF-β1 via ELISA), and MMP13 expression (IHC). qRT-PCR was used to measure Pros1, Axl, Mertk, and Rac1 mRNA expression in synovium, while Western blot was used to measure Protein S, Axl, MerTK, and Rac1 protein expression; MMP13 in cartilage was assessed by both methods.

RESULTS

ACLT successfully induced KOA, with severe cartilage degradation, synovial inflammation, elevated pro-inflammatory cytokines, and increased synovial apoptosis. EA significantly ameliorated cartilage damage (reduced Mankin's/OARSI scores, P < 0.01), decreased MMP13 expression (P < 0.05), attenuated synovitis (lower Krenn score, P < 0.01), reduced synovial apoptosis (P < 0.001), and shifted the cytokine profile toward an anti-inflammatory pattern (reduced IL-1β/TNF-α and increased IL-10/TGF-β1, P < 0.05). EA was also associated with reversal of the KOA-induced downregulation of Protein S-TAM-Rac1 axis-related molecules, with significantly increased synovial mRNA expression and partial restoration of protein expression.

CONCLUSION

EA showed anti-inflammatory and chondroprotective effects in this KOA model and was associated with changes in synovial Protein S-TAM (Axl/MerTK)-Rac1 axis-related molecules, with stronger evidence at the mRNA level than at the protein level. These molecular changes may be related to apoptotic cell clearance-related processes and inflammation resolution.