Development of an Effective Therapy for Alkaptonuria – Lessons for Osteoarthritis

Osteoarthritis (OA) is one of the major causes of disability and pain worldwide, yet despite a massive international research effort, no effective disease-modifying drugs have been identified to date. In this review, we put forward the proposition that greater focus on rarer forms of OA could lead to a better understanding of the pathogenesis of more common OA. We have investigated the severe osteoarthropathy of the ultra-rare disease alkaptonuria (AKU). In addition to the progress made in finding a treatment for AKU, our research has revealed important lessons for more common OA, including the identification of high-density mineralized protrusions (HDMPs), new pathoanatomical structures which may play an important role in joint destruction and pain in AKU and in OA. AKU is an inherited disorder of tyrosine metabolism, caused by genetic lack of the enzyme homogentisate 1,2 dioxygenase (HGD), which leads to failure to breakdown homogentisic acid (HGA). While most HGA is excreted over time, some of it is deposited as a pigment in connective tissues, a process described as ochronosis. Ochronotic pigment alters the mechanical properties of tissues, leading to inevitable joint destruction and frequently to cardiac valve disease. Until recently, there was no effective therapy for AKU, but preclinical studies demonstrated that upstream inhibition of tyrosine metabolism by nitisinone, a drug previously used in hereditary tyrosinaemia 1 (HT1), completely prevented ochronosis in AKU mice. This was followed by successful clinical trials which have resulted in nitisinone being approved for therapy of AKU by the European Medicines Agency, making AKU the only cause of OA for which there is an effective therapy to date. Study of other rare causes of OA should be a higher priority for researchers and funders to ensure further advances in understanding and eventual therapy of OA.