New Therapeutic Targets for Hyperuricaemia and Gout
Recent studies in diverse disciplines have led to significant advances in the understanding of the basic biology of hyperuricaemia and gout, with important implications for future treatment. These findings include genetic variation within SLC2A9 as a key regulator of urate homeostasis, and identification of urate—anion exchanger urate transporter 1 (URAT1) and other renal uric acid transporters. Recognition of urate as an endogenous danger signal and activator of the adaptive immune response suggests an important role for urate crystals in non-microbial immune surveillance. The central role of NALP3 inflammasome activation and IL-1β signalling in the initiation of the acute gout attack raises the possibility of new therapeutic targets. Disordered osteoclastogenesis in patients with chronic gout highlights potential therapies for prevention of joint damage. This review summarizes these findings and the potential relevance for future management of gout.
Gout is a common inflammatory disease of metabolic origin. This disorder is characterized by intermittent attacks of severe joint inflammation, and in the presence of persistent hyperuricaemia, development of tophaceous disease and chronic gouty arthropathy. The central role of hyperuricaemia and MSU crystal deposition in the pathogenesis of gouty inflammation has been recognized for decades (reviewed in), and new urate-lowering drugs such as febuxostat and PEG-uricase should lead to major improvements in long-term management of gout. However, many questions remain about the basic mechanisms of this disease. These questions include: why certain individuals are predisposed to hyperuricaemia; why certain hyperuricaemic individuals are predisposed to gout; how uric acid is handled by the renal tubule; what molecular pathways are involved in initiation of the acute gout attack; and what factors mediate joint damage in chronic gout. Recent laboratory research has shed light on a number of the issues. This review summarizes this research and focuses on the implications for future treatment of hyperuricaemia and gout.
Abstract and Introduction
Abstract
Recent studies in diverse disciplines have led to significant advances in the understanding of the basic biology of hyperuricaemia and gout, with important implications for future treatment. These findings include genetic variation within SLC2A9 as a key regulator of urate homeostasis, and identification of urate—anion exchanger urate transporter 1 (URAT1) and other renal uric acid transporters. Recognition of urate as an endogenous danger signal and activator of the adaptive immune response suggests an important role for urate crystals in non-microbial immune surveillance. The central role of NALP3 inflammasome activation and IL-1β signalling in the initiation of the acute gout attack raises the possibility of new therapeutic targets. Disordered osteoclastogenesis in patients with chronic gout highlights potential therapies for prevention of joint damage. This review summarizes these findings and the potential relevance for future management of gout.
Introduction
Gout is a common inflammatory disease of metabolic origin. This disorder is characterized by intermittent attacks of severe joint inflammation, and in the presence of persistent hyperuricaemia, development of tophaceous disease and chronic gouty arthropathy. The central role of hyperuricaemia and MSU crystal deposition in the pathogenesis of gouty inflammation has been recognized for decades (reviewed in), and new urate-lowering drugs such as febuxostat and PEG-uricase should lead to major improvements in long-term management of gout. However, many questions remain about the basic mechanisms of this disease. These questions include: why certain individuals are predisposed to hyperuricaemia; why certain hyperuricaemic individuals are predisposed to gout; how uric acid is handled by the renal tubule; what molecular pathways are involved in initiation of the acute gout attack; and what factors mediate joint damage in chronic gout. Recent laboratory research has shed light on a number of the issues. This review summarizes this research and focuses on the implications for future treatment of hyperuricaemia and gout.