Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability in the elderly, characterized by the progressive destruction of cartilage, synovial inflammation, and subchondral bone remodeling. While mechanical stress, metabolic derangements, and systemic inflammation are recognized contributors, accumulating evidence underscores the pivotal role of impaired macroautophagy/autophagy in disease pathogenesis. Autophagy declines with age, depriving chondrocytes and synovial cells of their cytoprotective capacity and rendering them vulnerable to apoptosis, matrix degradation, and inflammatory activation. Recent work has identified DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) as an extracellular hormone that represses autophagy through binding to the GABRG2/GABAARγ2 (gamma-aminobutyric type A receptor subunit gamma2) subunit of the GABA type A receptor. Plasma levels of DBI/ACBP are elevated in metabolic syndrome, obesity, diabetes, and aging, all known OA risk factors, and are upregulated in patients at risk of severe OA. In murine models of experimental OA, genetic deletion or antibody-mediated neutralization of DBI/ACBP mitigates joint inflammation, reduces cartilage destruction, and improves functional outcomes. These findings establish DBI/ACBP as a central pathogenic mediator linking aging-associated autophagy decline to osteoarthritis progression. Targeting DBI/ACBP represents a promising strategy to restore tissue homeostasis and modify the natural course of OA, with direct translational potential.
