Cross-regulation of inflammation and metabolic mechanisms in osteoarthritis: recent advances bridging the gap to novel treatments.

Osteoarthritis (OA) is a debilitating degenerative disease of the joints and one of the most prevalent joint disorders affecting millions of individuals worldwide. This disease is highlighted by significant morbidity owing to encumbering joint pain and functional impairment. OA ensues following disruption of normal homeostasis in the joint resulting from aging, metabolic changes, or as a consequence of joint injury (referred to as post-traumatic OA). These processes are largely driven by low-grade inflammation that gradually compromises the anabolic and protective activities of joint resident cells including chondrocytes, synovial fibroblasts (SFs) and immune cells. Ample research suggests that the process of cartilage deterioration is the endpoint of complex pathologic processes culminating with synovitis, subchondral bone sclerosis, osteophyte formation, aberrant remodeling, and ultimately articular cartilage degradation. There remains a great need for identifying early markers and a "window of opportunity" to enable timely interventions in OA. However, this effort is hampered by the complex nature of the disease and its comorbidities. Joint holistic approaches using recent unbiased multi-omic tools are currently at the forefront promising better understanding of OA development. Currently, there are no meaningful disease-modifying drugs to treat OA, with surgical procedures as the ultimate effective intervention for end stage OA patients. The disability, pain, and surgical costs associated with OA management position this disease among the costliest and onerous for our society. This mini review will highlight advances in the last two decades and major obstacles limiting progress in OA research with particular emphasis on metabolic and inflammatory comorbidities.