Progesterone Modulates Protein Synthesis in Osteoarthritic Fibroblast-like Synoviocytes

Knee osteoarthritis (OA) is highly prevalent in women and is characterized by structural joint alterations and synovial inflammatory processes that contribute to pain and impaired mobility. In a previous study, we identified a positive correlation between progesterone levels and pain intensity in postmenopausal women. However, the role of progesterone in synovial inflammation remains poorly understood. Therefore, this study aimed to characterize sex-specific differences in synovial tissue between postmenopausal women and age-matched men and to investigate the association between progesterone levels and the identified molecular profile. Whole blood and synovial tissue were collected from women and men with knee OA to assess plasma progesterone concentrations and the proteomic profiles of synovial tissue and isolated primary fibroblast-like synoviocytes (FLSs). The expression and localization of progesterone receptors were evaluated using RNAscope and immunofluorescence. FLS stimulated with physiological concentrations of progesterone were used for de novo protein synthesis assays. Quantitative proteomics of synovial tissue revealed enrichment of protein synthesis-related pathways in women compared to age-matched men, and isolated FLS from women with knee OA exhibited a pro-inflammatory and pro-fibrotic proteomic profile. Stratification by plasma progesterone levels identified two distinct patient groups, where lower progesterone levels were associated with pro-inflammatory signatures. The RNAscope analysis demonstrated increased transcriptional activity in synovial tissue from women with knee OA, localized to CD90⁺ sublining FLS. However, progesterone receptor expression at both the RNA and protein levels showed no sex-specific differences. Moreover, physiological concentrations of progesterone inhibited de novo protein synthesis in FLS isolated from men with knee OA. These findings underscore the hormonal context-dependent modulatory effects of progesterone on synovial inflammation and fibroblast activity. The study further highlights the importance of incorporating sex-specific hormonal profiles into OA patient stratification to support more precise and targeted therapeutic strategies.