Estrogen and progesterone exhibit distinct yet coordinated roles in the regulation of tendon extracellular matrix remodeling

Remodeling of the extracellular matrix (ECM) is required for the proper healing, strengthening, and maintenance of tendon tissue. There are well documented sex differences in tendon injury rates and healing outcomes, often attributed to either innate differences in tissue structure and resident cell signaling or the influence of sex hormones. However, these factors are rarely decoupled. Estrogen (17β-estradiol) and progesterone (P4) receptors are expressed in both male and female tendons and thus could participate in the remodeling process, but studies are extremely limited. Therefore, the objective of this work was to address whether biological sex differences are present in tendon remodeling and to determine the individual and combined roles of estrogen and progesterone in the remodeling process. We utilized an explant model of the flexor digitorum longus tendon harvested from young adult male and female mice to examine cell-mediated remodeling without disruption to the native environment. We found sex differences in tendon remodeling in the absence of hormonal stimulation, revealing how biological sex alone influences tendon health. We also demonstrate that the response to exogenous hormone delivery is sex-dependent, and that progesterone and estrogen serve complimentary yet independent roles. Overall, this work presents the first examination of sex-dependent matrix turnover in response to hormones and underscores the critical need for additional research in this area.