RESUMEN
Gout develops in four stages beginning with an asymptomatic increase in blood levels of uric acid. An acute gout attack is an expression of an underlying inflammatory process, which in the course of time is self-limiting. Without therapy monosodium urate crystals remain in the synovial fluid and synovial membrane and trigger more acute attacks. In the course of the disease monosodium urate crystals form deposits (tophi) leading in severe forms to irreversible joint deformities with loss of functionality. In 20% of cases gout leads to involvement of the kidneys. Overproduction of uric acid can cause nephrolithiasis. These stones can be composed of uric acid or calcium phosphate. Another form of kidney disease caused by gout is uric acid nephropathy. This is a form of abacterial chronic inflammatory response with deposition of sodium urate crystals in the medullary interstitium. Acute obstructive nephropathy is relatively rare and characterized by renal failure due to uric acid precipitation in the tubules because of rapid cell lysis that occurs, for example, with chemotherapy. There is a causal interdependence between the occurrence of hyperuricemia and hypertension. Uric acid activates the renin-angiotensin-aldosterone (RAA) system and inhibits nitric oxide (NO) with the possible consequence of a rise in systemic vascular resistance or arteriolar vasculopathy; however, uric acid is also an apparently independent risk factor for atherosclerosis. In contrast to young patients, the diagnosis of an acute gout attack in the elderly can be a challenge for the physician. Polyarticular manifestations and obscure symptoms can make it difficult to differentiate it from rheumatoid arthritis and calcium pyrophosphate deposition disease (CPPD). Aspiration of synovial fluid with visualization of urate crystals using compensated polarized light microscopy is the gold standard for diagnosis of acute gout. Moreover, analysis of synovial fluid enables a distinction from septic arthritis by Gram staining and bacterial culture. Soft tissue ultrasonography is useful to detect affected synovial tissue and monosodium urate crystals within the synovial fluid. Involvement of bone occurs relatively late in the disease so that xray images are not useful in the early stages but might be helpful in differential diagnostics. Dual energy computed tomography (CT) and magnetic resonance imaging (MRI) can be used for certain indications.
Asunto(s)
Artritis/fisiopatología , Pirofosfato de Calcio/sangre , Condrocalcinosis/diagnóstico , Gota/diagnóstico , Ácido Úrico/sangre , Anciano , Calcio , Condrocalcinosis/sangre , Condrocalcinosis/inmunología , Diagnóstico Diferencial , Gota/inmunología , Humanos , Hiperuricemia/complicacionesRESUMEN
Pseudogout is an autoinflammatory condition triggered by calcium pyrophosphate dehydrate (CPPD) crystal deposition in the joints. The innate immune system is irritated by and responds to the presence of the crystals with an inflammatory response. The synovial fluid contains activated inflammatory macrophages and neutrophil granulocytes. Several details of crystal-induced macrophage activation were recently uncovered, but very little is known about interactions of CPPD crystals with neutrophils. In this study, we show that human neutrophils engulf CPPD crystals and form large amounts of neutrophil extracellular traps (NETs) in vitro. Released extracellular DNA binds myeloperoxidase and citrullinated histone H4. CPPD crystal-stimulated neutrophils and their nuclear DNA undergo morphological changes characteristic for NET formation. The ERK/MEK signaling pathway, heat shock protein 90, PI3K, and an intact cytoskeleton are required for CPPD-induced NET formation. Blocking crystal-activated respiratory burst has, however, no effect on NETs. Human neutrophils release IL-1ß and IL-8 in response to CPPD crystals, and blocking CXCR2, the main IL-8R, diminishes NET formation. Proinflammatory cytokines, TNF-α, GM-CSF, and IL-1ß, increase NET release by the crystals. Enhanced bacterial killing by CPPD-induced NETs demonstrates their ability to cause cellular damage. Our work documents and provides details about extracellular trap release in human neutrophils activated by CPPD microcrystals. We suggest that crystal-triggered NET formation can be a novel contributor to inflammatory conditions observed in CPPD crystal-driven synovitis.
Asunto(s)
Pirofosfato de Calcio/inmunología , Condrocalcinosis/inmunología , Activación Neutrófila/inmunología , Neutrófilos/inmunología , Condrocalcinosis/patología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Fagocitosis/inmunologíaRESUMEN
OBJECTIVES: Killer cell lectin-like receptor G1 (KLRG1) is an NK cell marker also expressed on T cells showing an immunosenescent phenotype. KLRG1 binding to its ligand E-cadherin inhibits functional responses. It was recently shown that soluble E-cadherin (sE-cadherin) also influences KLRG1 signalling, although its involvement in arthritis is unknown. Our goal was to evaluate the contribution of KLRG1(+) T cells to synovitis. METHODS: Paired peripheral blood (PB) and synovial fluid (SF) mononuclear cells from 21 patients with spondyloarthritis (SpA) or rheumatoid arthritis (RA), eight with crystal-induced arthritis and 10 controls were obtained. T cells were characterised for KLRG1 expression directly ex vivo, while TNF-α/IFN-γ production was assessed after polyclonal stimulation. Assays of chemotaxis response towards SF were conducted. Additionally, sE-cadherin levels in our paired samples were determined. Moreover, TNF-α/IFN-γ production by antigen-specific T cells was evaluated in the presence of sE-cadherin. RESULTS: KLRG1(+) T cells were enriched in SF as opposed to PB of SpA and RA patients, which contrasts with results obtained in crystal-induced arthritides. KLRG1(+) T cells were more functionally active as opposed to KLRG1(-) T cells and migrated preferentially towards SpA and RA SF. sE-cadherin levels were higher in SF versus plasma. The presence of sE-cadherin enhanced the number of KLRG1(+) CD4(+) T cells able to produce TNF-α but not IFN-γ. CONCLUSIONS: sE-cadherin contributes to the local proinflammatory environment in the joint by favouring TNF-α production by KLRG1(+) CD4(+) T cells. This pathway seems to be operational in both SpA and RA, but not in crystal-induced arthritis.
Asunto(s)
Cadherinas/metabolismo , Condrocalcinosis/inmunología , Lectinas Tipo C/fisiología , Leucocitos Mononucleares/inmunología , Espondiloartritis/inmunología , Linfocitos T/inmunología , Transactivadores/fisiología , Factor de Necrosis Tumoral alfa/biosíntesis , Adulto , Anciano , Artritis Gotosa/inmunología , Artritis Gotosa/metabolismo , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Cadherinas/inmunología , Estudios de Casos y Controles , Células Cultivadas , Senescencia Celular/inmunología , Quimiotaxis/inmunología , Condrocalcinosis/metabolismo , Femenino , Humanos , Inflamación/inmunología , Interferón gamma/inmunología , Interferón gamma/metabolismo , Lectinas Tipo C/inmunología , Ligandos , Masculino , Persona de Mediana Edad , Receptores Inmunológicos , Espondiloartritis/metabolismo , Líquido Sinovial/citología , Sinovitis/inmunología , Linfocitos T/metabolismo , Transactivadores/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
If acute arthritis occurs in the elderly in addition to typical degenerative, load-related joint complaints, this is often induced by crystal deposition. The crystals lead to activation of the immune system resulting in acute inflammation. In addition to gout, calcium pyrophosphate deposition (CPPD) disease in particular must also be taken into consideration. Diagnostically important are imaging techniques, e.g. early specific alterations of cartilage can be shown by joint sonography and later calcium pyrophosphate crystals can be detected as cartilage calcification (chondrocalcinosis) by radiography. Important for the diagnosis of crystal arthropathy is usually the microscopic detection of specific crystals in the synovial fluid and is supported by exclusion of septic arthritis by arthrocentesis. In contrast to gout, which can be well controlled by the pharmaceutical lowering of uric acid levels, there is no causal therapy for CPPD disease so far. As CPPD may occur as a secondary effect in metabolic disorders, such as hyperparathyroidism or hemochromatosis, it seems to be important to search for the underlying disease. The following article presents the current knowledge on clinically relevant aspects of the pathogenesis, diagnosis and therapy of CPPD disease.
Asunto(s)
Condrocalcinosis/diagnóstico , Hallazgos Incidentales , Artrografía , Pirofosfato de Calcio/metabolismo , Cartílago Articular/inmunología , Cartílago Articular/patología , Condrocalcinosis/inmunología , Cristalización , Diagnóstico Diferencial , Progresión de la Enfermedad , Humanos , Articulaciones/inmunología , Articulaciones/patología , Líquido Sinovial/metabolismo , UltrasonografíaRESUMEN
Bone destruction is a common feature of inflammatory arthritis and is mediated by osteoclasts, the only specialized cells to carry out bone resorption. Aberrant expression of receptor activator of nuclear factor kappa ß ligand (RANKL), an inducer of osteoclast differentiation has been linked with bone pathology and the synovial fibroblast in rheumatoid arthritis (RA). In this manuscript, we challenge the current concept that an increase in RANKL expression governs osteoclastogenesis and bone destruction in autoimmune arthritis. We isolated human fibroblasts from RA, pyrophosphate arthropathy (PPA) and osteoarthritis (OA) patients and analyzed their RANKL/OPG expression profile and the capacity of their secreted factors to induce osteoclastogenesis. We determined a 10-fold increase of RANKL mRNA and protein in fibroblasts isolated from RA relative to PPA and OA patients. Peripheral blood mononuclear cells (PBMC) from healthy volunteers were cultured in the presence of RA, PPA and OA synovial fibroblast conditioned medium. Osteoclast differentiation was assessed by expression of tartrate-resistant acid phosphatase (TRAP), vitronectin receptor (VNR), F-actin ring formation and bone resorption assays. The formation of TRAP(+), VNR(+) multinucleated cells, capable of F-actin ring formation and lacunar resorption in synovial fibroblast conditioned medium cultures occured in the presence of osteoprotegerin (OPG) a RANKL antagonist. Osteoclasts did not form in these cultures in the absence of macrophage colony stimulating factor (M-CSF). Our data suggest that the conditioned medium of pure synovial fibroblast cultures contain inflammatory mediators that can induce osteoclast formation in human PBMC independently of RANKL. Moreover inhibition of the TNF or IL-6 pathway was not sufficient to abolish osteoclastogenic signals derived from arthritic synovial fibroblasts. Collectively, our data clearly show that alternate osteoclastogenic pathways exist in inflammatory arthritis and place the synovial fibroblast as a key regulatory cell in bone and joint destruction, which is a hallmark of autoimmune arthritis.
Asunto(s)
Artritis Reumatoide/inmunología , Condrocalcinosis/inmunología , Fibroblastos/metabolismo , Osteoartritis/inmunología , Osteoclastos/inmunología , Fosfatasa Ácida/genética , Fosfatasa Ácida/inmunología , Actinas/genética , Actinas/inmunología , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Resorción Ósea , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Condrocalcinosis/metabolismo , Condrocalcinosis/patología , Medios de Cultivo Condicionados/farmacología , Fibroblastos/inmunología , Fibroblastos/patología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Integrina alfaVbeta3/genética , Integrina alfaVbeta3/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Isoenzimas/genética , Isoenzimas/inmunología , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Osteoartritis/metabolismo , Osteoartritis/patología , Osteoclastos/citología , Osteoclastos/efectos de los fármacos , Osteoprotegerina/farmacología , Ligando RANK/antagonistas & inhibidores , Ligando RANK/genética , Ligando RANK/inmunología , Transducción de Señal/efectos de los fármacos , Líquido Sinovial/citología , Fosfatasa Ácida Tartratorresistente , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Recent advances have stimulated new interest in the area of crystal arthritis, as microcrystals can be considered to be endogenous "danger signals" and are potent stimulators of immune as well as non-immune cells. The best known microcrystals include urate (MSU), and calcium pyrophosphate (CPP) crystals, associated with gout and pseudogout, respectively. Acute inflammation is the hallmark of the acute tissue reaction to crystals in both gout and pseudogout. The mechanisms leading to joint inflammation in these diseases involve first crystal formation and subsequent coating with serum proteins. Crystals can then interact with plasma cell membrane, either directly or via membrane receptors, leading to NLRP3 activation, proteolytic cleavage and maturation of pro-interleukin-1ß (pro-IL1ß) and secretion of mature IL1ß. Once released, this cytokine orchestrates a series of events leading to endothelial cell activation and neutrophil recruitment. Ultimately, gout resolution involves several mechanisms including monocyte differentiation into macrophage, clearance of apoptotic neutrophils by macrophages, production of Transforming Growth Factor (TGF-ß) and modification of protein coating on the crystal surface. This review will examine these different steps.
Asunto(s)
Fosfatos de Calcio/inmunología , Condrocalcinosis/inmunología , Gota/inmunología , Inflamación/inmunología , Ácido Úrico/inmunología , Apoptosis/inmunología , Artritis Gotosa/inmunología , Biomarcadores/metabolismo , Proteínas Portadoras/inmunología , Condrocalcinosis/metabolismo , Condrocalcinosis/patología , Células Endoteliales/inmunología , Gota/metabolismo , Gota/patología , Humanos , Inflamasomas/inmunología , Inflamación/metabolismo , Inflamación/patología , Interleucina-1beta/inmunología , Macrófagos/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR , Neutrófilos/inmunología , Proteolisis , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
It is now well recognized that osteoarthritis (OA) synovial membrane presents inflammatory components. The aim of this work is to provide evidence that similar inflammatory mechanisms exist in synovial membrane (n = 24) obtained from three pathologies presenting altogether an inflammatory gradient: OA, chronic pyrophosphate arthropathy (CPPA) and rheumatoid arthritis (RA). Synovial biopsies were first characterized by a histological score based on synovial hyperplasia and infiltration of lymphocytes, plasma cells, polymorphonuclear and macrophages. All biopsies were also analyzed by 2D-nano-UPLC-ESI-Q-Orbitrap for protein identification and quantification. Protein levels were correlated with the histological score. Histological score was in the range of 3 to 8 for OA, 5 to 13 for CPPA and 12 to 17 for RA. Of the 4,336 proteins identified by mass spectrometry, 51 proteins were selected for their strong correlation (p < 0.001) with the histological score of which 11 proteins (DNAJB11, CALR, ERP29, GANAB, HSP90B1, HSPA1A, HSPA5, HYOU1, LMAN1, PDIA4, and TXNDC5) were involved in the endoplasmic reticulum (ER) stress. Protein levels of S100A8 and S100A9 were significantly higher in RA compared to OA (for both) or to CPPA (for S100A8 only) and also significantly correlated with the histological score. Eighteen complement component proteins were identified, but only C1QB and C1QBP were weakly correlated with the histological score. This study highlights the inflammatory gradient existing between OA, CPPA and RA synovitis either at the protein level or at the histological level. Inflamed synovitis was characterized by the overexpression of ER stress proteins.
Asunto(s)
Artritis Reumatoide/patología , Condrocalcinosis/patología , Estrés del Retículo Endoplásmico , Mediadores de Inflamación/metabolismo , Osteoartritis/patología , Proteínas/metabolismo , Sinovitis/patología , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Biomarcadores/análisis , Biomarcadores/metabolismo , Condrocalcinosis/inmunología , Condrocalcinosis/metabolismo , Difosfatos/metabolismo , Chaperón BiP del Retículo Endoplásmico , Femenino , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Masculino , Persona de Mediana Edad , Osteoartritis/inmunología , Osteoartritis/metabolismo , Proteínas/análisis , Proteoma/análisis , Proteoma/metabolismo , Estudios Retrospectivos , Sinovitis/inmunología , Sinovitis/metabolismoRESUMEN
The metabolic diseases gout and calciumpyrophosphate deposition (CPPD) (formerly: chondrocalcinosis/pseudogout) are crystal arthropathies which are caused by crystals in synovial fluid and in the case of gout also in periarticular structures. Today, in particular gout is considered as an auto-inflammatory process since phagocytosis of monosodium urate crystals by monocytes/macrophages results in the activation of the innate immune system by activation of the NRLP3-Inflammasome and consecutive secretion of the key cytokine interleukin-1ß and other pro-inflammatory cytokines. The prevalence of both crystal arthropathies rises with increasing age of patients. Most often they present clinically as an acute monarthritis of different locations. Beside typical clinical presentation, performance of ultrasonography, conventional X-Ray of joints and under special circumstances dual-energy-computer tomography could be also helpful diagnostic tools. There are EULAR guidelines describing the diagnostic algorithm for making right diagnosis. The arthrocentesis with microscopic detection of crystals is established diagnostic gold standard. Whereas crystals of monosodium urate could be very clearly be seen as relatively large intra- and extracellular needles with a strong birefringence in polarized light microscopy the detection of CPPD-crystals is more difficult. Those crystals are much smaller, showing weaker birefringence and are sometimes only seen with ordinary light microscopy. As both crystal diseases are mediated by IL-1 driven processes, the therapeutic intervention first target the acute inflammation consisting in colchicine, NSAIDs and glucocorticoids. Secondarily, in gout there are well established causal therapies to lower effectively serum urate levels below the target of 6âmg/dL (360âµmol/l). Unfortunately, those causal therapeutic options are still lacking in CPPD.
Asunto(s)
Condrocalcinosis/diagnóstico , Condrocalcinosis/terapia , Gota/diagnóstico , Gota/tratamiento farmacológico , Antiinflamatorios no Esteroideos/uso terapéutico , Condrocalcinosis/inmunología , Colchicina/uso terapéutico , Diagnóstico por Imagen , Glucocorticoides/uso terapéutico , Gota/inmunología , Humanos , Inflamasomas/inmunología , Interleucina-1beta/sangre , Macrófagos/inmunología , Monocitos/inmunología , Fagocitosis/inmunología , Ácido Úrico/sangreRESUMEN
The assessment of cytokines and their soluble receptors in the synovial fluid (SF) of inflammatory arthropathies may be useful in studying pathogenetic and immunoregulatory mechanisms underlying different diseases. The aim of this work was to study the cytokine network occurring in inflammatory arthropathies and to identify a cytokine profile which is characteristic of an immune-mediated synovitis. Levels of IL-12, as well as IL-4, IL-8, IL-10, IFN-gamma, sCD25, TNF-alpha and its soluble receptors were measured in the SF of various arthropathies, i.e. non-inflammatory arthropathies: "control" meniscus pathology (n = 21), osteoarthritis (n = 22) and chronic crystal arthritis (n = 9); a non-immune inflammatory arthropathy: acute crystal arthritis (n = 11); 2 immune inflammatory arthropathies: reactive arthritis (ReA) (n = 23) and rheumatoid arthritis (RA) (n = 44). SF levels of IL-10, TNF-alpha and sTNF-RII were found to be increased in the three inflammatory arthropathies compared to the "control" meniscus group. Within the inflammatory group, acute crystal arthritis was characterized by a significantly higher sTNF-RI/TNF-alpha ratio and ReA by a significantly lower sTNF-RII/TNF-alpha ratio compared to the two other diseases. The two immune arthropathies, RA and ReA, were characterized by increased SF levels of IL-12, sCD25 and of the sTNF-RII/sTNF-RI ratio. ReA differed however from RA by showing lower IL-8 and IL-4 levels, higher IFN-gamma levels and a higher IL-12/IL-10 ratio, suggesting a more prevalent Th1 profile in ReA SF. Our data indicate that the measurement of SF cytokines and soluble receptors may discriminate between each inflammatory arthropathy and might be useful in clinical practice.
Asunto(s)
Artritis/inmunología , Citocinas/biosíntesis , Interleucina-12/biosíntesis , Receptores de Interleucina-2/biosíntesis , Receptores del Factor de Necrosis Tumoral/inmunología , Líquido Sinovial/inmunología , Adulto , Anciano , Antígenos CD/inmunología , Artritis Reactiva/inmunología , Artritis Reumatoide/inmunología , Condrocalcinosis/inmunología , Femenino , Humanos , Interleucina-10/biosíntesis , Masculino , Persona de Mediana Edad , Prohibitinas , Receptores Tipo I de Factores de Necrosis Tumoral , Receptores Tipo II del Factor de Necrosis Tumoral , Células TH1/inmunología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
A prospective clinical and laboratory study was performed in thirty-four patients (twenty-two blacks, ten Puerto Ricans, and two whites) who had slipped capital femoral epiphysis in fifty-two hips. Although the majority of the laboratory studies were normal, all patients showed significant elevations of the serum immunoglobulins and C3 component of complement, with the highest values recorded for IgA. Urinary glycosaminoglycans were elevated in the few patients studied and increased proportionally with the duration of the disease. Nine (25 per cent) of the thirty-four patients had chondrolysis in thirteen hips. The male:female ratio in these nine patients was 0.8:1, compared with the ratio of 1.4:1 in all thirty-four patients. No additional biochemical abnormality was found in the patients with chondrolysis except for a greater elevation of the IgM fraction. These preliminary and tentative data suggest either that slipping of an epiphysis produces an antigen which induces an autoimmune state or that slipping is a localized manifestation of a generalized process resembling some form of connective-tissue disorder or inflammatory state. There is presumably a genetically determined sub-group of patients with this disorder who may have chondrolysis.
Asunto(s)
Condrocalcinosis/inmunología , Epífisis Desprendida/inmunología , Cabeza Femoral , Osificación Heterotópica/inmunología , Adolescente , Niño , Complemento C3/análisis , Epífisis Desprendida/orina , Etnicidad , Femenino , Glicosaminoglicanos/orina , Humanos , Hidroxiprolina/orina , Inmunoglobulinas/análisis , Masculino , Osificación Heterotópica/orina , Estudios Prospectivos , Líquido Sinovial/inmunologíaRESUMEN
Antigens of HLA loci A, B and DR were determined in 35 elderly patients with primary articular chondrocalcinosis and compared with a control population. The B15 antigen was present in 13 out of 35 patients, i.e. 37.1% as against 13% of controls (chi 2 = 13.4; pc = 0.05) and the BW21 antigen in 8 out of 35 patients, i.e. 22.8% as against 6.6% of controls (chi 2 = 10.25; pc less than 0.005). These results confirm those of a previous study carried out in the same unit, which showed a 41% incidence of HLA B15 antigen in patients with chondrocalcinosis. The HLA B15 antigen seems to be a marker of imbalanced binding with a susceptibility antigen. Calculation of the relative risk shows that an elderly subject with HLA B15 antigen if about 4 times more liable to articular chondrocalcinosis than a subject without this antigen.
Asunto(s)
Condrocalcinosis/inmunología , Antígenos HLA/análisis , Antígenos HLA-B , Anciano , Condrocalcinosis/genética , Antígeno HLA-B15 , HumanosAsunto(s)
Antígenos HLA/análisis , Inmunidad , Enfermedades Reumáticas/inmunología , Hiperplasia Suprarrenal Congénita , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/inmunología , Trastorno Bipolar/inmunología , Enfermedad Celíaca/inmunología , Condrocalcinosis/inmunología , Diabetes Mellitus Tipo 1/inmunología , Antígenos HLA/genética , Hemocromatosis/inmunología , Humanos , Inmunidad Innata , Lepra/inmunología , Esclerosis Múltiple/inmunología , Miastenia Gravis/inmunologíaRESUMEN
We describe herein the case of a 63-year-old man with pseudogout affecting multiple joints that was resistant to treatment with allopurinol, steroids, and antiinflammatory drugs. Based on recent data on the molecular mechanism of pseudogout that demonstrated overproduction of interleukin-1 (IL-1), we treated the patient with anakinra, an IL-1 receptor antagonist. The patient responded to treatment with anakinra within 2 weeks, with resolution of the signs and symptoms of pseudogout and normalization of levels of inflammation markers.
Asunto(s)
Antirreumáticos/administración & dosificación , Condrocalcinosis/tratamiento farmacológico , Proteína Antagonista del Receptor de Interleucina 1/administración & dosificación , Biomarcadores , Condrocalcinosis/inmunología , Condrocalcinosis/patología , Femenino , Humanos , Persona de Mediana EdadRESUMEN
PURPOSE OF REVIEW: Calcium pyrophosphate dihydrate and basic calcium phosphate crystals are common components of osteoarthritic synovial fluids and define subsets of patients with inflammatory or rapidly destructive arthritis. Recent literature concerning clinical and etiologic aspects of calcium pyrophosphate dihydrate and basic calcium phosphate crystal arthritis are reviewed. RECENT FINDINGS: Recent literature reminds us of the propensity of calcium pyrophosphate dihydrate deposition disease to mimic other syndromes affecting the elderly. Several new studies reinforce the prevalence and significance of extra-articular calcium pyrophosphate dihydrate deposits, and demonstrate the presence of basic calcium phosphate-like whitlockite crystals in intervertebral discs. Current work serves to increase our appreciation for the complex role of the putative pyrophosphate transporter, ANKH, in healthy and diseased cartilage. The application of newer radiographic techniques to the diagnosis of calcium pyrophosphate dihydrate deposition disease holds promise for easier and more accurate identification of these crystal deposits in vivo. Work demonstrating the efficacy of a crystal poison in an animal model of osteoarthritis provides good evidence for a pathogenic role of calcium crystals in osteoarthritis, and hope for new therapies for these diseases. SUMMARY: Continued work will further our understanding of these common crystals and their associated clinical syndromes.
Asunto(s)
Pirofosfato de Calcio/metabolismo , Condrocalcinosis/fisiopatología , Artritis/etiología , Condrocalcinosis/diagnóstico , Condrocalcinosis/inmunología , Humanos , Proteínas de Transporte de FosfatoRESUMEN
Crystal-induced inflammation pathogenesis is undergoing a transition with respect to monosodium urate, calcium pyrophosphate dihydrate, and even basic calcium phosphate crystals. It is now recognized that innate immunity could be involved in the earlier pathogenic events and that the inflammasome, along with other signaling pathways, is activated and results in interleukin-1 processing and secretion, ultimately activating cells as a paracrine or autocrine cytokine. Management of acute and chronic monosodium urate crystal-induced inflammation, namely gout, has been critically reviewed by a dedicated European working group, and on the behalf of the European League against Rheumatism, 12 evidence-based recommendations have been reported. Calcium pyrophosphate dihydrate chronic inflammation could benefit from colchicine and from methotrexate as an anti-inflammatory agent.
Asunto(s)
Condrocalcinosis/metabolismo , Gota/metabolismo , Inflamación/fisiopatología , Condrocalcinosis/tratamiento farmacológico , Condrocalcinosis/inmunología , Medicina Basada en la Evidencia , Gota/tratamiento farmacológico , Gota/inmunología , Humanos , Inflamación/tratamiento farmacológico , Ácido Úrico/farmacologíaRESUMEN
PURPOSE OF REVIEW: We examine the major genes in mice and humans involved in the pathogenesis of monosodium urate, calcium pyrophosphate dihydrate and hydroxyapatite crystal-induced arthritis. RECENT FINDINGS: Several genetic causes of renal disease associated with hyperuricemia and gout provide insight into genes involved in renal urate handling. Mutations or polymorphisms in exons 4 and 5 and intron 4 of urate transporter 1 may be independent genetic markers of hyperuricemia and gout. Genetic analysis supports the role of ANKH mutations in calcium pyrophosphate dihydrate-induced arthritis. ANKH gain-of-function mutations were confirmed by functional studies; however, the crystals formed in ATD5 cells were basic calcium phosphate, not calcium pyrophosphate dihydrate, underlying the significance of chondrocyte differentiation state and the factors regulating normal and pathological mineralization. Animal models have implicated a general model of crystal-induced inflammation involving innate immunity through the NALP3 (Natch domain, leucine-rich repeat, and PYD-containing protein 3) inflammasome signaling through the interleukin-1 receptor and its signaling protein myeloid differentiation primary response protein 88. SUMMARY: Genetic analysis has elucidated genes responsible for crystal formation and animal models have unveiled mechanisms in the development of crystal-induced arthritis. Future studies will hasten understanding of the pathology of crystal-induced arthritis and provide new therapies.
Asunto(s)
Artritis Gotosa/genética , Condrocalcinosis/genética , Hiperuricemia/genética , Inflamación/inducido químicamente , Animales , Artritis Gotosa/inmunología , Artritis Gotosa/fisiopatología , Condrocalcinosis/inmunología , Cristalización , Modelos Animales de Enfermedad , Humanos , Hidroxiapatitas/inmunología , Inflamación/genética , Inflamación/inmunología , Ratones , Insuficiencia Renal/genéticaRESUMEN
To determine whether synovial fluid (SF) macrophages isolated from the SF of osteoarthritis (OA), rheumatoid arthritis (RA) and pyrophosphate arthropathy (PPA) joints are capable of osteoclast formation, and to investigate the cellular and humoral factors required for this to occur, SF macrophages (CD14+) were isolated from the knee joint SF from patients with OA, RA and PPA and cultured for up to 14 days with macrophage-colony stimulating factor (M-CSF) and soluble receptor activator for nuclear factor-kappaB ligand (RANKL) or tumour-necrosis factor-alpha (TNFalpha) and interleukin-1alpha (IL-1alpha). Osteoclast differentiation was assessed by expression of tartrate-resistant acid phosphatase (TRAP) and vitronectin receptor (VNR), F-actin ring formation and lacunar resorption. Osteoclast formation and lacunar resorption was seen in RANKL-treated cultures of SF macrophages isolated from OA, RA and PPA joints with the largest amount of resorption noted in RA and PPA SF macrophage cultures. In TNFalpha/IL-1alpha-treated RA and PPA SF macrophage cultures, osteoclasts capable of lacunar resorption were also formed. Lacunar resorption was more extensive in RANKL than TNFalpha/IL-1alpha-treated cultures. These findings indicate that SF macrophages are capable of differentiating into mature osteoclasts capable of lacunar resorption. M-CSF in combination with RANKL or TNFalpha/IL-1alpha was required for osteoclast formation. As inflammatory synovial fluids contain an increase in the number of macrophages and an increase in the amounts of RANKL, TNFalpha and IL-1alpha, these findings suggest that one means whereby bone erosions may form in rheumatoid or crystal arthritis is by differentiation of synovial fluid macrophages into osteoclasts.
Asunto(s)
Artritis Reumatoide/fisiopatología , Condrocalcinosis/fisiopatología , Macrófagos/fisiología , Osteoartritis de la Rodilla/fisiopatología , Osteoclastos/fisiología , Líquido Sinovial/fisiología , Anciano , Artritis Reumatoide/inmunología , Resorción Ósea/inmunología , Resorción Ósea/fisiopatología , Proteínas Portadoras/inmunología , Proteínas Portadoras/fisiología , Diferenciación Celular/inmunología , Diferenciación Celular/fisiología , Células Cultivadas , Condrocalcinosis/inmunología , Femenino , Humanos , Interleucina-1/inmunología , Interleucina-1/fisiología , Articulación de la Rodilla/inmunología , Articulación de la Rodilla/fisiopatología , Receptores de Lipopolisacáridos/inmunología , Macrófagos/inmunología , Masculino , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/fisiología , Persona de Mediana Edad , Osteoartritis de la Rodilla/inmunología , Osteoclastos/inmunología , Osteogénesis/inmunología , Osteogénesis/fisiología , Fenotipo , Ligando RANK , Receptor Activador del Factor Nuclear kappa-B , Líquido Sinovial/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
Microcrystals of calcium pyrophosphate dihydrate (CPPD) and monosodium urate (MSU) deposited in synovium and articular cartilage initiate joint inflammation and cartilage degradation in large part by binding and directly activating resident cells. TLRs trigger innate host defense responses to infectious pathogens, and the expression of certain TLRs by synovial fibroblasts has revealed the potential for innate immune responses to be triggered by mesenchymally derived resident cells in the joint. In this study we tested the hypothesis that chondrocytes also express TLRs and that one or more TLRs centrally mediate chondrocyte responsiveness to CPPD and MSU crystals in vitro. We detected TLR2 expression in normal articular chondrocytes and up-regulation of TLR2 in osteoarthritic cartilage chondrocytes in situ. We demonstrated that transient transfection of TLR2 signaling-negative regulator Toll-interacting protein or treatment with TLR2-blocking Ab suppressed CPPD and MSU crystal-induced chondrocyte release of NO, an inflammatory mediator that promotes cartilage degeneration. Conversely, gain-of-function of TLR2 in normal chondrocytes via transfection was associated with increased CPPD and MSU crystal-induced NO release. Canonical TLR signaling by parallel pathways involving MyD88, IL-1R-associated kinase 1, TNF receptor-associated factor 6, and IkappaB kinase and Rac1, PI3K, and Akt critically mediated NO release in chondrocytes stimulated by both CPPD and MSU crystals. We conclude that CPPD and MSU crystals critically use TLR2-mediated signaling in chondrocytes to trigger NO generation. Our results indicate the potential for innate immunity at the level of the articular chondrocyte to directly contribute to inflammatory and degenerative tissue reactions associated with both gout and pseudogout.
Asunto(s)
Pirofosfato de Calcio/toxicidad , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Glicoproteínas de Membrana/metabolismo , Óxido Nítrico/biosíntesis , Receptores de Superficie Celular/metabolismo , Ácido Úrico/toxicidad , Proteínas Adaptadoras Transductoras de Señales , Animales , Antígenos de Diferenciación/metabolismo , Secuencia de Bases , Pirofosfato de Calcio/metabolismo , Bovinos , Células Cultivadas , Condrocalcinosis/etiología , Condrocalcinosis/inmunología , Condrocalcinosis/metabolismo , Condrocitos/inmunología , Cristalización , ADN Complementario/genética , Expresión Génica , Gota/etiología , Gota/inmunología , Gota/metabolismo , Humanos , Quinasa I-kappa B , Inmunidad Innata , Quinasas Asociadas a Receptores de Interleucina-1 , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/genética , Modelos Biológicos , Factor 88 de Diferenciación Mieloide , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores de Superficie Celular/genética , Receptores Inmunológicos/metabolismo , Transducción de Señal , Factor 6 Asociado a Receptor de TNF/metabolismo , Receptor Toll-Like 2 , Receptores Toll-Like , Ácido Úrico/metabolismo , Proteína de Unión al GTP rac1/metabolismoRESUMEN
Total hemolytic complement (CH50) was measured in 174 synovial fluids (SF) to determine its diagnostic and and prognostic value. SF CH50 was reduced relative to serum CH50 in 61% of patients with rheumatoid arthritis and 60% of patients with crystal-induced arthritis. There was no correlation of SF CH50 levels with disease duration, SF leukocyte count, presence of IgM rheumatoid factor, or radiologic evidence of erosions.