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Monocyte chemoattractant protein-1 exacerbates diabetic rotator cuff tears by driving synovial inflammation via the
Yingming Wang1, Xianzhe Gu2, Jun Tu3
1Department of Orthopedic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Department of Orthopedic Surgery, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui, China.
Background:
Patients with diabetes exhibit a higher incidence and more severe manifestations of rotator cuff tears (RCTs), yet the etiopathogenesis remains poorly defined. This study investigates the pathological characteristics and mechanisms underlying diabetic rotator cuff pathology.
Methods:
The clinical study enrolled 30 patients with diabetes and RCTs, along with 30 matched nondiabetic controls with RCTs. Preoperative functional scores and magnetic resonance imaging data were collected. Synovial samples were obtained during surgery, and inflammatory mediators were quantified by enzyme-linked immunosorbent assay. In the animal study, diabetes was induced in mice using a high-fat diet and streptozotocin. Synovium-specific Ccl2 knockout mice and wild-type controls underwent subacromial impingement surgery. Postoperative assessments included gait analysis, pain threshold testing, biomechanical evaluation, as well as histological and molecular analyses. Statistical significance was set at P < .05.
Results:
We observed significantly elevated synovial inflammation and MCP-1 expression in patients with diabetes and RCTs. These findings were recapitulated in diabetic murine models of rotator cuff injury, which exhibited exacerbated synovitis (with increased IFN-γ, IL-1β, and TNF-α), marked pain, functional impairment, and accelerated tendon degeneration. Notably, synovium-specific Ccl2 knockdown attenuated the diabetes-associated degenerative progression. Mechanistically, MCP-1 signals primarily through the CCR2 receptor to enhance the release of inflammatory mediators. Subsequent activation of the MAPK/ERK pathway drives pro-inflammatory M1 macrophage polarization, thereby aggravating synovitis and contributing to severe pain, functional disability, and tendon degeneration. In vivo pharmacological inhibition of MCP-1 significantly reversed diabetes-induced synovial inflammation and improved pain thresholds.
Conclusions:
Diabetes exacerbates rotator cuff degeneration through MCP-1/CCR2 signaling, which may activate ERK/MAPK and drive M1 macrophage polarization. Targeting this axis could be a potential therapeutic approach for diabetic RCTs.
