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RAGE-dependent NF-κB inflammation processes in the capsule of frozen shoulders

YANO TOSHIHISA 東北大学

2020.03.25

概要

Background: Inflammation with fibrosis is one of the primary pathologies of FS. However, the etiology of frozen shoulder (FS) remains unknown. Advanced glycation end-products (AGEs) cause cross-linking and stabilization of collagen and are reported to increase in FS. The present study aimed to elucidate the pathogenesis of FS by evaluating the receptor of AGE (RAGE)-dependent pathways.

Methods: Tissue samples of the rotator interval (RI), coracohumeral ligament (CHL), and anterior-inferior glenohumeral ligament (IGHL) were collected from 33 patients with FS, presenting with severe stiffness, and 25 patients with rotator cuff tears (RCT) as controls. Gene expression levels of RAGE, high-mobility group box 1 (HMGB1), Toll-like receptor 2 (TLR2), TLR4, S100 calcium binding protein A1 (S100A1), S100B, nuclear factor-κ B (NF-κB), and cytokines were determined using quantitative real-time polymerase chain reaction. The immunoreactivity of carboxymethyllysine (CML), pentosidine, and RAGE were also evaluated. CML and pentosidine were evaluated using high-performance liquid chromatography (HPLC).

Results: Gene expression levels of RAGE, HMGB1, TLR2, TLR4, S100A1, S100B, and NF-κB were significantly greater in the CHL and IGHL tissue from the FS group compared to those in the RCT group (RAGE in CHL, p = 0.006; in IGHL, p = 0.016; HMGB1 in CHL, p = 0.008; in IGHL, p < 0.001; TLR2 in CHL, p = 0.044; in IGHL, p = 0.004; TLR4 in CHL, p = 0.021; in IGHL, p = 0.027; S100A1 in CHL, p = 0.001; in IGHL, p = 0.008; S100B in CHL, p = 0.001; in IGHL, p = 0.012; NF-κB in CHL, p = 0.001; in IGHL, p = 0.035). Further, the immunoreactivity of RAGE and CML was stronger in the CHLs and IGHLs from the FS group compared to those from the RCT group. Pentosidine was found to be weakly immunostained in the CHLs, IGHLs, and RIs from the FS group. HPLC results show that CML levels were significantly greater in the CHLs and IGHLs from the FS group compared to those from the RCT group (CHL, p = 0.011; IGHL, p = 0.008).

Conclusion: The results indicated that in AGEs, CML, rather than pentosidine, exerted a more pronounced effect on FS pathology. AGEs, HMGB1, and S100 protein are supposed to bring inflammation with fibrosis in FS, by binding to RAGE and activating NF-κB signaling pathways. Hence, suppression of these pathways could provide a potential treatment option for FS.

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