JSES - 2026-06-03 - Journal Article
MCP-1 Exacerbates Diabetic Rotator Cuff Tear by Driving Synovial Inflammation via MAPK/ERK-Mediated Macrophage Polarization.
Wang Y, Gu X, Tu J, Xu B
Topics
Key Takeaway
Synovial MCP-1/CCR2-MAPK/ERK-driven M1 macrophage polarization is mechanistically responsible for accelerated rotator cuff degeneration in diabetes, with synovium-specific Ccl2 knockout and pharmacological MCP-1 inhibition both attenuating this degenerative progression in a murine model.
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Summary
This study asked whether MCP-1-driven synovial inflammation mediates the worse rotator cuff pathology seen in diabetic patients. Synovial ELISA from 30 diabetic versus 30 non-diabetic RCT patients confirmed elevated MCP-1, IFN-γ, IL-1β, and TNF-α in the diabetic group; streptozotocin/high-fat diet murine models with subacromial impingement surgery recapitulated these findings. Synovium-specific Ccl2 knockout and pharmacological MCP-1 inhibition both reduced synovitis, improved pain thresholds, and attenuated tendon degeneration, identifying the MCP-1/CCR2/MAPK-ERK/M1 macrophage axis as the operative mechanism.
Key Limitation
The clinical component provides no postoperative functional or structural outcomes, so whether elevated synovial MCP-1 independently predicts retear or worse patient-reported outcomes after repair remains untested.
Original Abstract
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 non-diabetic controls with RCTs. Preoperative functional scores and MRI data were collected. Synovial samples were obtained during surgery, and inflammatory mediators were quantified by enzyme-linked immunosorbent assay (ELISA). 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 < 0.05
RESULTS
We observed significantly elevated synovial inflammation and MCP-1 expression in patients with diabetes and rotator cuff tears. 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.
LEVEL OF EVIDENCE
Basic Science Study, Molecular Biology.