Faculty Bibliography

Osteoarthritis (OA) can be a progressive, disabling disease, leading to diminished quality of life, and, for over 500,000 individuals annually in the US, total joint replacement. The etiology of OA will vary among individuals, with potential roles for systemic factors (such as genetics and obesity) as well as for local biomechanical factors (such as muscle weakness, joint laxity and traumatic injury). Joint deterioration occurs over extended periods of time, and the diverse molecular mechanisms that mediate pathogenic events of early, mid and late disease are not yet fully understood. The success of biologic therapies in the treatment of rheumatoid arthritis has demonstrated that the blockade of a single dominant cytokine or regulatory molecule can prevent cartilage destruction in a complex disease, and has raised expectations that mechanism-based treatments could also be developed for patients with OA. In this review, we will address the biological mechanisms that mediate structural damage in OA and examine current targets that are candidates for disease modification. The challenges to drug development and the obstacles to disease modification strategies will also be addressed

The osteoarthritis disease process affects not only the cartilage but also the entire joint structure, including the synovium, bone and periarticular muscles. Characteristically, abnormal biomechanical forces result in an imbalance between chondrocyte anabolic and catabolic pathways, which ultimately leads to progressive joint destruction. Within cartilage and synovium, pro-inflammatory cytokines, particularly IL-1b and TNF-a, auto-catalytically stimulate their own production and induce chondrocytes to produce additional catabolic mediators, including proteases, chemokines, nitric oxide, and prostaglandins. The success of targeted biological therapy in rheumatoid arthritis has taught that the blockade of a single dominant cytokine can lead to remarkable clinical benefit, even in complex disease. The effectiveness of biologicals in inflammatory arthritides as disease modifying agents has increased the likelihood that similar strategies can be developed to target specific molecular mechanisms in osteoarthritis (OA). However, since the clinical development program for disease-modifying OA drugs (DMOADs) is complicated by the slow progression of disease in many patients, the introduction of DMOADs will be greatly enhanced by advances in imaging and biomarkers that serve as validated surrogate endpoints for meaningful clinical outcomes