Recent advances in understanding the pathogenesis of ochronosis

Alkaptonuria (AKU) is an iconic disease caused by deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD). Deficiency results in an increase in the circulating concentration of homogentisic acid (HGA), which over time is deposited as pigmented polymers in tissues including sclera, heart valves and cartilage, a process described as ochronosis. Joint ochronosis causes severe, early onset osteoarthritis. Studies on ex vivo tissue samples, in vitro cell cultures and mouse models of AKU indicate that tissues are initially resistant to ochronosis and become susceptible possibly following mechanical or oxidative damage and/or local metabolic changes. There is a lack of effective biomarkers to monitor the progression of ochronosis and response to potential therapies but a disease severity index for AKU has recently been developed. Current studies are evaluating the efficacy of the potential therapy nitisinone in AKU. Research on ochronosis has led to the identification of several previously unrecognised pathophysiological features of the osteoarthritis phenotype.