Aging microenvironment in osteoarthritis focusing on early-stage alterations and targeted therapies

Abstract Osteoarthritis (OA) is one of the most common degenerative and age-related diseases in joints, which affects 654 million people worldwide. Current therapies could not fundamentally reverse the pathologic process of OA due to the complex pathogenesis. Although OA mechanisms have been investigated on a large scale over the past decade, the OA pathology correlated with aging-associated changes is still largely unrevealed. Therefore, in-depth analysis of the aging microenvironment and aging-related molecular mechanisms in OA may offer additional strategies for clinical prevention and treatment. In this review, we discuss the potential pathogenesis of OA in light of aging-associated changes and summarize three main components of the aging microenvironment of the OA joint: immune homeostatic imbalance, cellular senescence, and stem cell exhaustion, which could be induced by aging and further exacerbate OA progression. Additionally, it is emphasized that immune homeostatic imbalance appears before established OA, which occurs in the early stage and is the therapeutic window of opportunity for better clinical outcomes. Importantly, we evaluate recent therapeutic targets and promising interventions against these components, as well as the challenges and prospects for precise and individualized therapies of OA patients, which we believe would guide the construction of novel combined strategies targeting aging-related factors against OA for better treatments in the future.