Abstract
Tendinopathy is a highly prevalent musculoskeletal pathology associated with incremental injury as result of repetitive microtrauma. We sought to explore the physiological significance of stromal “activation” signatures in a human model of tendinopathy. Torn supraspinatus tendon and matched intact subscapularis tendon biopsies were collected from patients undergoing shoulder surgery while healthy tendon was collected from patients undergoing anterior cruciate ligament (ACL) reconstruction. Expression of stromal activation markers was analyzed at transcript/protein level using qRT-PCR and immunohistochemistry. Gene expression of stromal activation markers was silenced by siRNA-mediated knockdown or induced by IL-1β stimulation. Expression of “activation” markers podoplanin, VCAM-1 and CD248 was identified in human tendon tissue. Podoplanin and VCAM-1 expression were significantly increased in tendinopathic tissue. Knockdown of podoplanin and VCAM-1 in normal and tendinopathic tenocytes did not have any significant effect on expression of matrix genes COL1A1, COL3A1, TNC, or DCN. Similarly, no changes in release of inflammatory mediators IL-6, IL-8, and CCL2 were observed in podoplanin/VCAM-1 knockdown cultures. Our data suggest that silencing expression of stromal “activation” markers does not affect the intrinsic inflammatory profile or matrix regulatory behavior of tenocytes. We propose that the term “activation” is more appropriately reflected by alterations in tenocyte behavior that induce changes in the stromal microenvironment and overall tissue architecture rather than identification through potentially arbitrary phenotypic traits.
Highlights
Tendinopathy is a highly prevalent musculoskeletal pathology associated with overuse injury
We found no significant effect of podoplanin or VCAM1 knockdown alone on release of IL-6, IL-8 (Figure 4C,D, Figure 5C,D), or CCL2 (Figure 4E,F, Figure 5E,F) in normal or tendinopathic tenocytes compared with untransfected tenocytes and scramble transfection control
We conclude that tenocytes lacking expression of “activation” markers podoplanin and VCAM-1 do not display any discernible changes in typical disease-associated behaviors and remain pathogenic
Summary
Tendinopathy is a highly prevalent musculoskeletal pathology associated with overuse injury. Tendinopathies account for 30%-50% of sporting injuries and a large portion of orthopedic referrals from primary care.[1,2] Dysregulated matrix repair elicited by persistent pathological inflammation is the main causative factor in the development of established tendinopathy.[3] Injured tendons display irregular tissue architecture and weakened biomechanical properties, primarily. The stroma was considered to be immunologically inert and exist purely as a tissue-specific scaffold that participates in wound healing responses.[6] Excessive loading of tendons was considered the main pathological stimulus for degeneration, conferred by the mechanosensing properties of tenocytes.[7] Tenocytes are fibroblast-like cells that comprise the main cellular component of the tendon stroma. It has been postulated that recruitment, influx, and retention of immune cells are controlled by cytokine and chemokine gradients created by resident stromal cells.[8]
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