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Microcrystal-induced joint inflammation, joint damage and the inflammasome

Applicant So Alexander Kai-Lik
Number 130085
Funding scheme Project funding (Div. I-III)
Research institution Service de Rhumatologie, Médecine Physique et Réhabilitation Hôpital Nestlé - CHUV
Institution of higher education University of Lausanne - LA
Main discipline Pathophysiology
Start/End 01.06.2010 - 30.09.2013
Approved amount 288'000.00
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Keywords (7)

inflammasome; inflammation; crystal-induced arthritis; osteoarthritis; arthritis; joint disease; gout

Lay Summary (English)

Lead
Lay summary
Microcrystals in the medical context refer to particles in the micrometer size range that originate from biological components. Examples include urate, composed of monosodium urate(MSU), cholesterol, calcium pyrophosphate and basic calcium phosphate (BCP). All these crystals have been associated with pathological conditions and our understanding of how crystals cause disease may help in advancing management and treatment of these conditions.Among rheumatic diseases, three conditions are clearly linked to microcrystal deposition: acute arthritis in gout, where crystals of MSU form in the joint because of excessive levels of uric acid in the circulation; calcium pyrophosphate deposition in the joint cartilage and the finding of BCP crystals in the cartilage and joint fluids of cases of advanced osteoarthritis (OA). OA is the most common cause of joint disease in man and our understanding of the events leading up to joint damage is poor. Recent research has demonstrated a novel pathway that these microcrystals can cause inflammation by the activation of the inflammasome. However, it is likely that other pathways of inflammation and cellular activation are involved and this forms the basis of our research plan.In the SNF proposal, we plan to study two major aspects of how microcrystals cause joint disease. In the first part, we will study the modification factors that influence how MSU crystals elicit an inflammatory response and how these factors may explain the different phases of gout in man. We wish to identify if there are any protective factors that can reduce inflammation and how these can be manipulated in the clinical setting to reduce the clinical burden. Secondly, we will study the influence of BCP crystals on the progression of OA, making use of experimental models of OA in animals to determine the pathways that initiate and potentiate joint inflammation and damage. This research may lead to novel therapeutic pathways for gout and OA.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Pathogenic role of basic calcium phosphate crystals in destructive arthropathies
Ea Korng, Busso Nathalie (2013), Pathogenic role of basic calcium phosphate crystals in destructive arthropathies, in PLOS One, 8(2), e57352.
Update on gout 2012
So Alexander, Busso Nathalie (2012), Update on gout 2012, in Joint Bone Spine, 79(6), 539-543.
A pilot study of IL-1 inhibition in acute calcific periarthritis of the shoulder
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.
Gout: why is this curable disease so seldom cured?
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.
Microcrystals as DAMPs and their role in joint inflammation
Busso Nathalie, So Alexander (2012), Microcrystals as DAMPs and their role in joint inflammation, in Rheumatology, 51(7), 1154-1160.
The etiology and management of gout
Pazar Maldonado Bori, So Alexander (2012), The etiology and management of gout, in Zeitschrift Rheumatologie, 71(2), 127-136.
Basic calcium phosphate crystals induce NLRP3 inflammasome activation: the in vitro and in vivo face to face
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.
Increased interleukin-10 production by ASC-deficient CD4+ T cells impairs bystander T-cell proliferation
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.
Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study
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.
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
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.
Octacalcium phosphate crystals induce inflammation in vivo through interleukin-1 but independent of the NLRP3 inflammasome in mice
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.
Basic calcium phosphate crystals induce monocyte/macrophage IL-1beta secretion through the NLRP3 inflammasome in vitro
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.
Epidemiology: Gout-bad for the heart as well as the joint
So Alexander (2010), Epidemiology: Gout-bad for the heart as well as the joint, in Nature reviews. Rheumatology, 6(7), 386-387.
Osteoarthritis: Crystal-gazing into the pathogenesis of osteoarthritis
So Alexander, Busso Nathalie (2010), Osteoarthritis: Crystal-gazing into the pathogenesis of osteoarthritis, in Nature reviews. Rheumatology, 7(12), 688-689.
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
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.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual General Meeting 2013 Deutsche Gesellschaft Innere Medizin 07.04.2013 Wiesbaden
Annual Meeting Société Française de Rhumatologie, 2012 09.12.2012 Paris
American College of Rheumatology Annual meeting 2012 02.11.2012 Washington DC
EULAR Annual meeting 06.06.2012 Berlin, Germany
European Crystal Network 08.03.2012 Paris, France
International Forum for the Evaluation of Cardiovascular care 08.02.2012 Nice. France
EFIS-EJI course 28.11.2011 Paris, France
Annual meeting of the ACR 2011 04.11.2011 Chicago, USA


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
EULAR annual meeting 25.05.2011 London
European Crystal Network 10.03.2011 Paris


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Crystallising options for inflammation International Innovation International 01.05.2012
Media relations: print media, online media Le supplice de la goutte Migros Magazine Western Switzerland 05.03.2012

Associated projects

Number Title Start Funding scheme
153010 Crystals, joint inflammation and osteoarthritis 01.04.2014 Project funding (Div. I-III)

Abstract

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.
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