Abstract
Inflammation and extracellular matrix (ECM) disorganization following the rotator cuff tendon injuries (RCTI) delay the repair and healing process and the molecular mechanisms underlying RCTI pathology are largely unknown. Here, we examined the role of HMGB1 and NLRP3 inflammasome pathway in the inflammation and ECM disorganization in RCTI. This hypothesis was tested in a tenotomy-RCTI rat model by transecting the RC tendon from the humerus. H&E and pentachrome staining revealed significant changes in the morphology, architecture and ECM organization in RC tendon tissues following RCTI when compared with contralateral control. Severity of the injury was high in the first two weeks with improvement in 3–4 weeks following RCTI, and this correlated with the healing response. The expression of proteins associated with increased HMGB-1 and upregulation of NLRP3 inflammasome pathway, TLR4, TLR2, TREM-1, RAGE, ASC, Caspase-1, and IL-1β, in the first two weeks following RCTI followed by decline in 3–4 weeks. These results suggest the association of inflammatory responses and ECM disorganization with HMGB1 upregulation and NLRP3 inflammasome activation in the RC tendons and could provide novel target(s) for development of better therapeutic strategies in the management of RCTI.
Highlights
Inflammation and extracellular matrix (ECM) disorganization following the rotator cuff tendon injuries (RCTI) delay the repair and healing process and the molecular mechanisms underlying RCTI pathology are largely unknown
The expression of proteins associated with increased HMGB-1 and upregulation of NLRP3 inflammasome pathway, TLR4, TLR2, Triggering receptors expressed on myeloid cell-1 (TREM-1), Receptor for advanced glycation end products (RAGE), ASC, Caspase-1, and IL-1β, in the first two weeks following RCTI followed by decline in 3–4 weeks
These results suggest the association of inflammatory responses and ECM disorganization with HMGB1 upregulation and NLRP3 inflammasome activation in the RC tendons and could provide novel target(s) for development of better therapeutic strategies in the management of RCTI
Summary
Inflammation and extracellular matrix (ECM) disorganization following the rotator cuff tendon injuries (RCTI) delay the repair and healing process and the molecular mechanisms underlying RCTI pathology are largely unknown. The expression of proteins associated with increased HMGB-1 and upregulation of NLRP3 inflammasome pathway, TLR4, TLR2, TREM-1, RAGE, ASC, Caspase-1, and IL-1β, in the first two weeks following RCTI followed by decline in 3–4 weeks These results suggest the association of inflammatory responses and ECM disorganization with HMGB1 upregulation and NLRP3 inflammasome activation in the RC tendons and could provide novel target(s) for development of better therapeutic strategies in the management of RCTI. The upregulation of inflammatory cytokines and increased oxidative stress has been tightly associated with RCTI pathology which hurdles the healing responses These cytokines are believed to be involved in the maintenance of tendon matrisome homeostasis by regulating the expression of extracellular matrix (ECM) genes, especially type 1 collagen by tenoblasts and tenocytes[3]. The initial signal which triggers HMGB1 release is unknown
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