Celecoxib, Beyond Anti-inflammation, Alleviates Tendon-Derived Stem Cell Senescence in Degenerative Rotator Cuff Tendinopathy

Abstract

Background: Degenerative rotator cuff tendinopathy (RCT) is associated with the senescence of tendon-derived stem cells (TDSCs). Nonsteroidal anti-inflammatory drugs have been demonstrated to alleviate age-associated inflammation (inflamm-aging)–induced cellular senescence of skeletal stem/progenitor cells. However, whether they can alleviate degenerative RCT through reducing inflamm-aging–related TDSC senescence is still unknown. Purpose: To assess whether celecoxib can prevent the inflamm-aging–related cellular senescence of TDSCs. Study Design: Controlled laboratory study. Methods: TDSCs were isolated from degenerative RCT tendons (S-TDSCs) and healthy hamstring tendons (Y-TDSCs), and the cellular senescence of TDSCs was evaluated. Thereafter, the senescent TDSC-conditioned medium (SEN-CM) was collected to culture Y-TDSCs with or without celecoxib. The effects of celecoxib on TDSC senescence were examined by assaying the expression of aging-related markers. Furthermore, the level of the NF-κB pathway was determined by Western blot analysis to explore the underlying mechanism. Its effects on preventing dysfunction of inflamm-aging–induced senescent TDSCs were also determined using multilineage differentiation assay. Results: S-TDSCs showed increased senescence-associated β-galactosidase activity and enhanced expression of γ-H2AX, p21CIP1A, p16INK4A, and senescence-associated secretory phenotype factors. SEN-CM accelerated the senescence progress of Y-TDSCs, resulting in an increase in senescence markers. To some extent, celecoxib treatment could prevent the detrimental effects of inflamm-aging on Y-TDSCs. The level of the NF-κB pathway was increased in the SEN-CM group but decreased with the use of celecoxib. Moreover, the reduced senescence of TDSCs resulted in preservation of the TDSC tenogenic potential. Conclusion: Celecoxib treatment can prevent inflamm-aging–induced TDSC senescence, which holds potential for alleviating the development of degenerative RCT. Clinical Relevance: In addition to relieving the symptoms of patients with RCT, treatment with celecoxib, a common nonsteroidal anti-inflammatory drug, may defer the development of RCT and prevent rotator cuff tears by delaying TDSC senescence.