Tissue & cell · 2026
Formation of post-traumatic and non-traumatic knee joint contracture: Role of macrophage polarization in joint capsule and skeletal muscle.
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Wang Feng, Bai Fan, Zhou Ting, Liu He, Wu Ding-Jiang, Zhou Yun, Li Wen
Аннотация
PURPOSE: This study investigated how differential macrophage polarization dynamics drive the severity of post-traumatic joint contracture (PTJC) compared to non-traumatic joint contracture (NTJC).
METHODS: We first performed a bioinformatic analysis intersecting the human dataset GSE135854 with macrophage polarization gene sets to identify core pathogenic targets. Subsequently, rat models of surgically-induced post-traumatic contracture and immobilization-only non-traumatic contracture were established. This study assessed temporal changes in joint range of motion, histopathological fibrosis, macrophage polarization dynamics, and molecular pathways including TLR4/MyD88/NF-κB signaling and fibrotic mediators.
RESULTS: Bioinformatic profiling identified 1137 core genes linking macrophage polarization to arthrofibrosis, which were enriched in immune-related biological processes and the NF-kappa B signaling pathway. Clinically, TLR4 and MYD88 were downregulated in end-stage human fibrosis, suggesting a temporal resolution of early inflammatory signals. In rat models, PTJC exhibited significantly more severe contracture and aggressive fibroproliferative remodeling compared to NTJC. Mechanistically, PTJC induced a robust early surge in M1 macrophages via TLR4/MyD88/NF-κB pathway activation, followed by a delayed, pathological M2 response. In contrast, NTJC showed milder macrophage dynamics. The discrepancy between early-stage rat models (upregulation) and end-stage clinical samples (downregulation) underscores the TLR4 axis as an early initiator of the fibrotic cascade.
CONCLUSION: Trauma drives severe contracture via a specific, aggressive fibroproliferative cascade involving dysregulated macrophage plasticity and regional tissue crosstalk. Effective management of PTJC requires phase-specific strategies: targeting the early TLR4-mediated M1 surge and modulating the late-stage pathological M2 response, distinct from the prophylactic needs of NTJC.
METHODS: We first performed a bioinformatic analysis intersecting the human dataset GSE135854 with macrophage polarization gene sets to identify core pathogenic targets. Subsequently, rat models of surgically-induced post-traumatic contracture and immobilization-only non-traumatic contracture were established. This study assessed temporal changes in joint range of motion, histopathological fibrosis, macrophage polarization dynamics, and molecular pathways including TLR4/MyD88/NF-κB signaling and fibrotic mediators.
RESULTS: Bioinformatic profiling identified 1137 core genes linking macrophage polarization to arthrofibrosis, which were enriched in immune-related biological processes and the NF-kappa B signaling pathway. Clinically, TLR4 and MYD88 were downregulated in end-stage human fibrosis, suggesting a temporal resolution of early inflammatory signals. In rat models, PTJC exhibited significantly more severe contracture and aggressive fibroproliferative remodeling compared to NTJC. Mechanistically, PTJC induced a robust early surge in M1 macrophages via TLR4/MyD88/NF-κB pathway activation, followed by a delayed, pathological M2 response. In contrast, NTJC showed milder macrophage dynamics. The discrepancy between early-stage rat models (upregulation) and end-stage clinical samples (downregulation) underscores the TLR4 axis as an early initiator of the fibrotic cascade.
CONCLUSION: Trauma drives severe contracture via a specific, aggressive fibroproliferative cascade involving dysregulated macrophage plasticity and regional tissue crosstalk. Effective management of PTJC requires phase-specific strategies: targeting the early TLR4-mediated M1 surge and modulating the late-stage pathological M2 response, distinct from the prophylactic needs of NTJC.