Investigating the association between uterine fibroids and weight‑bearing joint osteoarthritis based on a bidirectional Mendelian randomization study

Uterine fibroids (UFs) are benign smooth-muscle tumors of the uterus that commonly affect women of reproductive age and can influence systemic hormonal and inflammatory states. Osteoarthritis (OA) is a chronic degenerative disease of weight-bearing joints (e.g., hip and knee) and a leading cause of pain and disability. Shared hormonal and immune pathways plausibly link UFs and OA; however, whether a genetic or biological association exists remains unclear. The present study utilized Mendelian randomization (MR) analysis combined with experimental validation to investigate a potential genetic and biological association between UF and OA in weight-bearing joints. Bidirectional MR analyses were carried out using a genome-wide association study to evaluate the potential genetic association between UFs, hip OA (hOA) and knee OA (kOA). The primary method used in the present study was inverse variance weighting, which was supported by complementary approaches including weighted median and MR-Egger. Heterogeneity and pleiotropy were assessed using the Cochran's Q test, MR-Egger intercept and MR-pleiotropy residual sum and outlier. Additionally, sensitivity analyses were conducted using leave-one-out analysis. Furthermore, experimental validation was carried out using a Transwell co-culture system to investigate the effects of UF cells (UFCs) on OA chondrocytes. MR analysis revealed a significant inverse genetic association between UFs and the risk of hOA. However, no genetic association was observed between UFs and kOA. Reverse MR analyses did not support a genetic association between hOA or kOA with UF. Furthermore, experimental results demonstrated that UFCs significantly mitigated OA cartilage degeneration by inhibiting the degradation of Collagen II and Aggrecan at the mRNA level. The present study indicated a potential novel genetic association between UF and hOA, suggesting a potential biological association likely mediated by the tumor microenvironment (such as hormonal or immune alterations), which warrants further mechanistic investigation.