Extracellular HMGB-1 activates inflammatory signaling in tendon cells and tissues

Abstract

Background: Increasing evidence indicates that secretion of high mobility group box 1 protein (HMGB-1) is functionally associated with tendinopathy development. However, the underlying effect and mechanism of extracellular HMGB-1 on tendon cells are unclear. Methods: We tested the effect of exogenous HMGB-1 on cell growth, migration, and inflammatory signaling responses with isolated rat Achilles tendon cells. Also, we studied the role of extracellular HMGB-1, when administrated alone or in combination with mechanical overloading induced by intensive treadmill running (ITR), in stimulating inflammatory effects in tendon tissues. Results: By using in vitro and in vivo models, we show for the first time that exogenous HMGB-1 dose-dependently induces inflammatory reactions in tendon cells and tendon tissue. Extracellular HMGB-1 promoted redistribution of HMGB-1 from the nucleus to the cytoplasm, and activated canonical nuclear factor kappa B (NF-κB) signaling and mitogen-activated protein kinase (MAPK) signaling. Short-term administration of HMGB-1 induced hyper-cellularity of rat Achilles tendon tissues, accompanied with enhanced immune cell infiltration. Additional ITR to HMGB-1 treatment worsens these responses, and application of HMGB-1 specific inhibitor glycyrrhizin (GL) completely abolishes such inflammatory effects in tendon tissues. Conclusion: Collectively, these results confirm that HMGB-1 plays key roles in the induction of tendinopathy. Our findings improve the understanding of the molecular and cellular mechanisms during tendinopathy development, and provide essential information for potential targeted treatments of tendinopathy.

Optimal Extraction of Xuetongsu and its Mechanisms in Inhibiting RA Synovial Hyperplasia: Intervention in Migration and Apoptosis of Synovial Cells

“…Furthermore, the upregulation of caspase-3 and Bax, coupled with the downregulation of Bcl-2, provided evidence supporting the inhibitory effects of XTS on RAFLS cell migration and the promotion of apoptosis. [31].…”

Inflammatory mechanisms linking obesity and tendinopathy

“…Regarding the possible mechanisms of HMGB1 on tendinopathy, HMGB1 was reported to increase the mobility, proliferation, as well as the expression of IL-1β, IL-6, IL-33, CCL2, CXCL12, TNF-α, MMP3. MMP13, collagen type 3, tenascin C and decorin in tenocytes via TLR4/NF-kB/MAPK activation [ 93 , 102 ]. The short-term administration of HMGB1 was reported to induce hyper-cellularity of rat Achilles tissues, accompanied with enhanced immune cell infiltration [ 102 ].…”

“…MMP13, collagen type 3, tenascin C and decorin in tenocytes via TLR4/NF-kB/MAPK activation [ 93 , 102 ]. The short-term administration of HMGB1 was reported to induce hyper-cellularity of rat Achilles tissues, accompanied with enhanced immune cell infiltration [ 102 ].…”

“…Moreover, mechanical overloading in vivo induced the release of HMGB1 into tendon extracellular matrix and induced tendon inflammation in a mouse treadmill running model [ 126 , 127 ]. In addition, the administration of glycyrrhizin or metformin, both are HMGB1 inhibitors, inhibited the development of Achilles tendinopathy induced by long-term intensive treadmill running in mice [ 102 , 126 , 127 ].…”

“…References can be made to the interventions under trial for other obesity-induced co-morbidities. Indeed, there were some early in vitro and in vivo studies on the effects of metformin and glycyrrhizin for the treatment of tendon overuse with encouraging results [ 102 , 126 , 127 ]. However, recent studies have shown that statins use was associated with higher risk of trigger finger and shoulder tendinopathy, possibly through MMP release [ [143] , [144] ], suggesting that the medication used for the management of obesity may also do harm more than good on tendons.…”