Molecular Mechanism Study of Medial Open-Wedge High Tibial Osteotomy in Treating Medial Compartment Osteoarthritis of the Knee by Improving the Intra-Articular Environment

Background: Medial compartment osteoarthritis (MCOA) of the knee, often linked to varus malalignment, leads to increased medial tibiofemoral stress, accelerating cartilage degradation and inflammation. Medial open-wedge high tibial osteotomy (MOWHTO) corrects this alignment to relieve symptoms, but its molecular and biomechanical mechanisms are underexplored. Hypothesis/Purpose: We hypothesized that MOWHTO reduces intra-articular stress, thereby modulating inflammatory, catabolic, and autophagic pathways to improve joint homeostasis. The purpose was to assess clinical, molecular, biomechanical, and in vitro effects in MCOA patients. Study Design: Prospective clinical cohort study (n=63) combined with in vitro biomechanical simulations . Methods: Patients (aged 40–65 years, Kellgren-Lawrence grade I–III MCOA) unresponsive to conservative therapy underwent MOWHTO. Pre- and 12-month post-operative assessments included clinical scores (KSS, IKDC, VAS), imaging (X-ray for mMPTA/FTA/PTS; MRI T2 mapping), and molecular analyses of synovial fluid, cartilage, and synovium (ELISA for IL-1β/TNF-α/CTX-II; qRT-PCR/Western blot/immunofluorescence for MMP-13/COL2A1/ACAN/LC3/Beclin-1; metabolomics). In vitro, chondrocytes/synovial cells from surgical samples were subjected to high (10–15 kPa) vs. low (3–5 kPa) cyclic compression simulating pre-/post-MOWHTO stress, with interventions (XAV939/BAY11-7082/rapamycin) targeting Wnt/β-catenin, NF-κB, and autophagy. Finite element analysis evaluated stress; bioinformatics mapped pathways. Results: MOWHTO improved KSS (63.79→90.32), IKDC (55.68→83.19), and VAS (5.48→0.95; all p<0.001), corrected alignment (mMPTA 84.02°→90.53°; p<0.01), and enhanced cartilage integrity (T2 55.3→48.7 ms; p<0.01). Molecularly, IL-1β/TNF-α/MMP-13/CTX-II decreased (35–50%; p<0.01), while COL2A1/ACAN/LC3/Beclin-1 increased (2–2.5-fold; p<0.01). In vitro, low stress reduced catabolism/inflammation and boosted autophagy; inhibitors/inducers confirmed pathway mediation. Bioinformatics showed downregulated inflammatory lipids and upregulated anabolism. Conclusion: MOWHTO alleviates biomechanical stress, suppresses inflammation/cartilage degradation, and enhances autophagy, with IL-1β, MMP-13, and LC3 as biomarkers. Clinical Relevance: These findings validate MOWHTO's efficacy for early MCOA, guiding patient selection and monitoring via biomarkers to optimize outcomes and delay arthroplasty.