Do we understand sex-related differences governing dimorphic disease mechanisms in preclinical animal models of osteoarthritis?

Research conducted using murine preclinical models of osteoarthritis (OA) over the last three decades has brought forth many exciting developments showcasing mechanisms and pathways that ‎drive disease pathogenesis. These models have identified therapeutic targets that can be modulated via innovative biologicals and pharmaceuticals. However, many of these ‎approaches have failed to translate to humans and reach the clinic. This commentary aims to highlight some of the key ‎hurdles in the translation of novel findings using preclinical OA models. While the focus of this commentary is on OA-related joint structural aberrations dictated by chondrosenescence, other signaling mechanisms have been shown to be affected by sexual dimorphism (i.e TGFβ signalling, EGFR/integrin α1β1 and Trpv4). Preclinical models of OA mainly utilize male mice ‎due to their capacity to capitulate a fast progressing OA structural phenotype compared to ‎female mice. This experimental trend has overlooked and ignored the sex-related effects of numerous mechanisms affecting joint structure, that ‎influence OA structural progression. Future work should focus on analysing both sexes ‎and understanding sex-related differences, which will enable ‎us to gain a better understanding of the progression of OA based on sex-related mechanistic discrepancies.