The Obesogenic Joint Revisited: Mechanobiological, Microbial, and Epigenetic Interfaces in the Pathogenesis of Early-Onset Osteoarthritis

<ns3:p>Background Obesity has been established as a risk factor of osteoarthritis (OA) and this is largely due to the higher mechanical loading on weight bearing joints. However, recent evidence indicates that earlier onset of obesity increases the rate of osteoarthritis formation through the influence of a complex obesogenic joint environment. Methods We performed a narrative literature review to analyze the mechanistic connections between obesity and early-onset osteoarthritis. PubMed, Scopus, and Web of Science were searched to identify relevant human and animal studies (published 2010-2025), with a focus on biomechanical overload research, systemic inflammatory effects of adiposity, gut-joint axis (microbiome dysbiosis) and obesity-related epigenetic reprogramming research. Results Mechanical stress on joints was observed to grow with excess body weight, which resulted in the rapid wearing of cartilages and subchondral bone. Obesity is also associated with a systemic pro-inflammatory condition (through adipose-derived cytokines and adipokines), which has the potential to stimulate osteoarthritis in non-weight-bearing joints. Moreover, gut microbiome dysbiosis associated with obesity could impair the integrity of the intestinal barrier, which permits the entry of endotoxins into the circulation and worsens synovial inflammation and cartilage erosion. Chronic inflammation and abnormal mechanical loading of obesity may cause epigenetic changes in chondrocytes and synovial cells (including DNA hypermethylation and microRNA changes) that increase catabolic-related responses of joint tissues predisposing individuals to earlier osteoarthritis Conclusions The problem of obesity causes osteoarthritis in a number of interconnected pathways other than increased load such as systemic inflammation, changes in the gut microbiome, and the reprogramming of epigenetics in joint tissues. The realization of this multi-factorial interplay is the rationale behind the necessity for holistic solutions.</ns3:p>