Osteoarthritis (OA) is a degenerative joint disease characterized by irreversible loss of articular cartilage. There is no cure for OA. Current treatments provide, at best, relief from pain and inflammation associated with the more advanced phases of disease but they do not target the OA progression because the molecular mechanisms are not well understood. A major challenge in OA is halting cartilage damage before disease progression begins. Cartilage hypertrophy occurs early in OA, but its role in OA progression is not well defined. In the proposed research we aim to investigate the role of FoxA factors as potential regulators of articular cartilage hypertrophy and OA progression in both human OA and a murine model of this disease. To reach this objective, we propose three aims.
In Aim 1, we will determine whether loss of FoxA factors prevents cartilage hypertrophy and degradation following surgical destabilization of the knee joint.
In Aim 2 we will ascertain whether FoxA2-driven chondrocyte hypertrophy primes the articular cartilage for inflammatory cytokine signaling, or whether inflammation develops in the articular cartilage independent of hypertrophy.
In Aim 3, we will determine whether FoxA2 positive cells give rise to the foci where future osteoarthritic lesions will develop and whether FoxA factors are induced in deteriorating articular cartilage from patients with OA. Altogether, these results will provide a strong basis for development of drugs to treat patients with osteoarthritis. The long term goal is a better understanding of the pathogenic mechanisms underlying OA onset and progression, in hopes of discovering potential targets for pharmacological intervention.
In this project the investigators study the role of transcriptional regulators of cartilage hypertrophy and the potential crosstalk between hypertrophy and inflammation in hopes of gaining insights in the pathogenic mechanisms that underlie osteoarthritis progression. The results of the study will help discovery of drugs for treatment of patients with osteoarthritis.