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 study 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 capitalized on a three-dimensional explant model to directly examine hormone-mediated ECM turnover without disruption to the native cell microenvironment. Flexor digitorum longus tendon explants harvested from mature male and female mice were stimulated continuously with chemically endogenous hormones for 1 week, after which we examined synthesis and degradation of matrix components as well as overall tissue composition. We found sex differences in the absence of hormonal stimulation, indicating a chromosomal influence to observed functional sex differences. We also demonstrate that the response to exogenous hormone delivery is sex-dependent, and that progesterone and estrogen serve complementary yet independent roles. Overall, this study demonstrates the importance of hormones in the regulation of tissue structure and function and underscores the critical need for additional research in this area.