inflammasome; inflammation; crystal-induced arthritis; osteoarthritis; arthritis; joint disease; gout
Ea Korng, Busso Nathalie (2013), Pathogenic role of basic calcium phosphate crystals in destructive arthropathies, in PLOS One
, 8(2), e57352.
So Alexander, Busso Nathalie (2012), Update on gout 2012, in Joint Bone Spine
, 79(6), 539-543.
Zufferey Pascal, So Alexander (2012), A pilot study of IL-1 inhibition in acute calcific periarthritis of the shoulder, in Ann Rheum Dis
, 72(3), 465-467.
Doherty Michael, Jansen Tim, Nuki George, Pascual Eliseo, Perez-Ruiz Fernando, Punzi Leonardo, So Alexander, Bardin Thomas (2012), Gout: why is this curable disease so seldom cured?, in Ann Rheum Dis
, 71(11), 1765-1770.
Busso Nathalie, So Alexander (2012), Microcrystals as DAMPs and their role in joint inflammation, in Rheumatology
, 51(7), 1154-1160.
Pazar Maldonado Bori, So Alexander (2012), The etiology and management of gout, in Zeitschrift Rheumatologie
, 71(2), 127-136.
Ea Korng, So Alexander, Lioté Frédéric, Busso Nathalie (2011), Basic calcium phosphate crystals induce NLRP3 inflammasome activation: the in vitro and in vivo face to face, in Proc Natl Acad Sci U S A
, 108(50), E1361-E1362.
Narayan Sharmal, Kolly Laeticia, So Alexander, Busso Nathalie (2011), Increased interleukin-10 production by ASC-deficient CD4+ T cells impairs bystander T-cell proliferation, in Immunology
, 134(1), 33-40.
Schlesinger Naomi, So Alexander (2011), Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study, in Annals Rheumatic Diseases
, 70(7), 1264-1271.
Schlesinger Naomi, So Alexander (2011), Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat Gouty Arthritis by suppressing inflammation: results of a randomized, dose, in Arthritis Research Therapy
, 13(2), R53-R53.
Narayan Sharmal, Pazar Borbala, Ea H. Korng, Kolly Laeticia, Bagnoud Nathaliane, Chobaz Véronique, Liote Frédéric, Vogl T, Holzinger Dirk, So Alexander, Busso Nathalie (2011), Octacalcium phosphate crystals induce inflammation in vivo through interleukin-1 but independent of the NLRP3 inflammasome in mice, in Arthritis & Rheumatism
, 63(2), 422-433.
Pazàr Borbala, Ea H. Korng, Narayan Sharmal, Kolly Laeticia, Bagnoud Nathaliane, Chobaz Véronique, Roger Thierry, Lioté Frédéric, So Alexander, Busso Nathalie (2011), Basic calcium phosphate crystals induce monocyte/macrophage IL-1beta secretion through the NLRP3 inflammasome in vitro, in Journal of Immunology
, 186(4), 2495-2502.
So Alexander (2010), Epidemiology: Gout-bad for the heart as well as the joint, in Nature reviews. Rheumatology
, 6(7), 386-387.
So Alexander, Busso Nathalie (2010), Osteoarthritis: Crystal-gazing into the pathogenesis of osteoarthritis, in Nature reviews. Rheumatology
, 7(12), 688-689.
Schlesinger Naomi, So Alexander, Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions, in Annals of the Rheumatic Diseases
Microcrystals are potent inducers of inflammation and clinically cause acute arthritis such as gout and pseudogout. The mechanisms underlying this reaction are partially understood in the case of monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals, but not at all clear for basic calcium phosphate (BCP) crystals. The NLRP3 inflammasome is activated to process and secrete mature IL1ß by MSU and CPPD crystals, and may be a key step in triggering inflammation cascades in microcrystal-induced arthritis. In most instances, microcrystals induce an acute inflammatory response that resolves spontaneously over 10-14 days, in the absence of specific medical intervention. How the inflammatory response is modulated is not well understood. Different factors that have been shown to affect MSU crystal-induced inflammation include the protein coating on the crystal surface, as well as cellular factors, in particular the maturation stage of the monocyte/macrophage. It is likely that these factors contribute to the self-limiting nature of gout. With increasing knowledge of the functions of the inflammasome, we hypothesize that activity of this protein complex and how it interacts with exogenous and endogenous signals play a key part in the control of the acute inflammatory response. Understanding how acute inflammation is regulated would be important not just in the treatment of gout and pseudogout, but may have applications in other inflammatory diseases.Besides acute inflammation, microcrystals are also linked to degenerative joint diseases, and a catabolic effect of crystals on chondrocytes has been demonstrated. Epidemiological data strongly suggests that both CPPD and BCP crystals are associated with disease progession in osteoarthritis (OA), and one mechanism may be through chronic inflammation. This question has not been extensively studied up to now and with the new knowledge of the inflammasome, we propose to investigate the mechanisms that underlie BCP and CPPD induced inflammation as well as studying the effects of BCP and CPPD in joint pathology in animal models of OA. The questions we wish to address in this project include the role of the NLRP3 inflammasome in chronic inflammation induced by BCP crystals; the contribution of IL1 signalling to the development and progression of OA and identification of the involvement of other inflammatory pathways and mediators. A better understanding of these fundamental pathways may open up novel therapeutic areas for a disease that has lacked effective treatments up to now. Based on preliminary data we have already generated from our own laboratory, and an ongoing collaboration with Prof Jurg Tschopp at the Institute of Biochemistry of the University of Lausanne, we are well equipped to investigate these questions and hopefully generate new hypotheses and results that would lead to advances in treatment of these joint diseases.