Multiple strategies, one mission: mesenchymal stromal cell-based mechanisms of action in osteoarthritis.

Osteoarthritis (OA) is a cross-species, multifactorial joint disease characterized by the progressive degeneration of articular cartilage, morphological remodeling of the subchondral bone, and inflammatory and fibrotic changes of the joint capsule. These alterations arise from chronic, often subclinical, inflammatory processes and dysregulated cellular homeostasis, leading to profound shifts in the cellular and extracellular composition of the joint organ. Although the mechanisms driving persistent inflammation are only partially understood, their impact on all joint-associated tissues is well-established. Mesenchymal stromal cells (MSCs) have gained increasing attention as therapeutic candidates for OA due to their immunomodulatory and potentially regenerative capacities. Increasing evidence indicates that MSCs exert their effects predominantly through indirect mechanisms, including paracrine signaling, the release of extracellular vesicles, mitochondrial transfer, and modulation of innate and adaptive immune responses. This review summarizes current insights into how these mechanisms may act within the articular microenvironment to attenuate cartilage degeneration and promote tissue repair in OA. Herein, we consider the effects of MSCs on different cell types and tissues within the joint, and highlight mitochondrial transfer as an emerging mechanism through which MSCs may regenerate and protect them, thereby contributing to the rescue of joint homeostasis.