Sex considerations in regenerative rehabilitation strategies for the treatment of knee osteoarthritis

Regenerative rehabilitation is a promising field aimed at harnessing the regenerative potential of stem-cell therapeutics to maximize functional recovery. Here, we outline recent advancements in the field of regenerative rehabilitation for treating knee osteoarthritis (KOA) and we highlight sex-specific considerations to promote knowledge translation to the clinic. A systematic review suggests that sexual dimorphism in the efficacy of regenerative rehabilitation approaches for the treatment of KOA may be partly attributed to the functional decline of female mesenchymal stem cells (MSCs) over the lifespan, particularly after menopause. These declines are likely to be accompanied by poor clinical outcomes. While evidence is far from adequate, physical therapeutics have emerged as a means to promote estrogen signaling in MSCs, potentially reversing menopause-related MSC dysfunction. This study calls for actions to dissect the effects of menopause, together with physical therapeutics, on stem-cell therapeutics toward the development of effective regenerative rehabilitation approaches.