RESUMEN
The frequency and risk factors for the development of diastolic dysfunction (DD) in patients with CPPD and OA have not been studied. The objective of this study was to determine the frequency and identify risk factors (RF) for the development of DD of the left and right ventricles (LV and RV) in patients with calcium pyrophosphate crystal deposition disease (CPPD) and osteoarthritis (OA). The study included 26 patients with CPPD and with knee OA 18-65 years old, matched in age and gender, without cardiovascular disease (CVD), type 2 diabetes mellitus (DM2), and rheumatic diseases. Conventional risk factors (TRF) of CVD were assessed, and echocardiography was performed. The frequency of DD in patients with CPPD and OA was quite high and almost did not differ in both groups: it was detected in 19 patients, of which 11 (42%) had CPPD and 8 (31%) had OA (p = 0.39). Type 1 LV DD was detected in 10 (39%) patients with CPPD and in 8 (31%) with OA (p = 0.11); type 1RV DD was detected in 8 (31%) patients with CPPD and in 7 (27%) patients with OA (p = 0.17); and type 1 LV DD and RV DD was detected in 7 (27%) patients with both CPPD and with OA. DD types 2 and 3 were not detected in both groups. There were no differences in both groups in CV risk factors, except for the level of CRP (it was higher in CPPD) (p = 0.03). In the CPPD group, mean values of LV E/E' (p = 0.02), LVDT (p = 0.03), LVMI (p = 0.04) were significantly higher than in patients with OA. On the contrary, in patients with OA, indices EDV (p = 0.004) and TVC (p = 0.02) were higher. There were direct correlations between diastolic function indices and the following factors in CPPD: LVL, PWLV and PTH level (r = 0.7, p <0.005), LV E' and PTH level (r = 0.7, p < 0.005). Inverse correlations were found between the level of PTH and IS (r = -0.5, p < 0.005), LVMI (r = -0.5, p < 0.005), and the level of vitamin D and VDDT (r = -0.6, p < 0.005). Direct correlations in OA were found between the level of CRP and PVAdiast (r = 0.6, p < 0.005), and the level of sUA (r = 0.7, p < 0.005), and the level of vitamin D and E/E'LV (r = 0.6, p < 0.005). A high prevalence of LV and RV DD was found in patients with CPPD and OA. The presence of DD in CPPD was associated with lower vitamin D levels, and in OA with a higher level of sUA and a lower level of PTH.
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Condrocalcinosis , Osteoartritis , Humanos , Persona de Mediana Edad , Masculino , Femenino , Adulto , Anciano , Condrocalcinosis/metabolismo , Condrocalcinosis/fisiopatología , Condrocalcinosis/sangre , Osteoartritis/fisiopatología , Osteoartritis/metabolismo , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/diagnóstico por imagen , Ventrículos Cardíacos/fisiopatología , Factores de Riesgo , Disfunción Ventricular Derecha/fisiopatología , Disfunción Ventricular Derecha/diagnóstico por imagen , Diástole , AdolescenteRESUMEN
OBJECTIVES: To study the mechanism by which the readthrough mutation in TNFRSF11B, encoding osteoprotegerin (OPG) with additional 19 amino acids at its C-terminus (OPG-XL), causes the characteristic bidirectional phenotype of subchondral bone turnover accompanied by cartilage mineralization in chondrocalcinosis patients. METHODS: OPG-XL was studied by human induced pluripotent stem cells expressing OPG-XL and two isogenic CRISPR/Cas9-corrected controls in cartilage and bone organoids. Osteoclastogenesis was studied with monocytes from OPG-XL carriers and matched healthy controls followed by gene expression characterization. Dual energy X-ray absorptiometry scans and MRI analyses were used to characterize the phenotype of carriers and non-carriers of the mutation. RESULTS: Human OPG-XL carriers relative to sex- and age-matched controls showed, after an initial delay, large active osteoclasts with high number of nuclei. By employing hiPSCs expressing OPG-XL and isogenic CRISPR/Cas9-corrected controls to established cartilage and bone organoids, we demonstrated that expression of OPG-XL resulted in excessive fibrosis in cartilage and high mineralization in bone accompanied by marked downregulation of MGP, encoding matrix Gla protein, and upregulation of DIO2, encoding type 2 deiodinase, gene expression, respectively. CONCLUSIONS: The readthrough mutation at CCAL1 locus in TNFRSF11B identifies an unknown role for OPG-XL in subchondral bone turnover and cartilage mineralization in humans via DIO2 and MGP functions. Previously, OPG-XL was shown to affect binding between RANKL and heparan sulphate (HS) resulting in loss of immobilized OPG-XL. Therefore, effects may be triggered by deficiency in the immobilization of OPG-XL Since the characteristic bidirectional pathophysiology of articular cartilage calcification accompanied by low subchondral bone mineralization is also a hallmark of OA pathophysiology, our results are likely extrapolated to common arthropathies.
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Calcinosis , Cartílago Articular , Condrocalcinosis , Células Madre Pluripotentes Inducidas , Humanos , Remodelación Ósea , Calcinosis/metabolismo , Cartílago Articular/metabolismo , Condrocalcinosis/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Mutación , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ligando RANK/metabolismoRESUMEN
Calcium pyrophosphate (CPP) deposition disease (CPPD) is a form of CPP crystal-induced arthritis. A high concentration of extracellular pyrophosphate (ePPi) in synovial fluid is positively correlated with the formation of CPP crystals, and ePPi can be upregulated by ankylosis human (ANKH) and ectonucleotide pyrophosphatase 1 (ENPP1) and downregulated by tissue non-specific alkaline phosphatase (TNAP). However, there is currently no drug that eliminates CPP crystals. We explored the effects of the histone deacetylase (HDAC) inhibitors (HDACis) trichostatin A (TSA) and vorinostat (SAHA) on CPP formation. Transforming growth factor (TGF)-ß1-treated human primary cultured articular chondrocytes (HC-a cells) were used to increase ePPi and CPP formation, which were determined by pyrophosphate assay and CPP crystal staining assay, respectively. Artificial substrates thymidine 5'-monophosphate p-nitrophenyl ester (p-NpTMP) and p-nitrophenyl phosphate (p-NPP) were used to estimate ENPP1 and TNAP activities, respectively. The HDACis TSA and SAHA significantly reduced mRNA and protein expressions of ANKH and ENPP1 but increased TNAP expression in a dose-dependent manner in HC-a cells. Further results demonstrated that TSA and SAHA decreased ENPP1 activity, increased TNAP activity, and limited levels of ePPi and CPP. As expected, both TSA and SAHA significantly increased the acetylation of histones 3 and 4 but failed to block Smad-2 phosphorylation induced by TGF-ß1. These results suggest that HDACis prevented the formation of CPP by regulating ANKH, ENPP1, and TNAP expressions and can possibly be developed as a potential drug to treat or prevent CPPD.
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Pirofosfato de Calcio , Condrocalcinosis , Pirofosfato de Calcio/metabolismo , Condrocalcinosis/tratamiento farmacológico , Condrocalcinosis/genética , Condrocalcinosis/metabolismo , Condrocitos/metabolismo , Inhibidores de Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Pirofosfatasas/genética , Pirofosfatasas/metabolismoRESUMEN
BACKGROUND Calcium pyrophosphate dihydrate deposition disease includes a variety of clinical syndromes, including acute calcium pyrophosphate (CPP) crystal arthritis. Most patients with CPP crystal arthritis have a primary/idiopathic form presenting with severe pain, swelling, and stiffness. COVID-19 infection, which originated in China in December 2019, required extraordinary efforts to develop and test new vaccines to halt the pandemic. The Vaxzervria vaccine has shown excellent safety and efficacy in phase 3 trials with a mechanism based on the expression of the SARS-CoV-2 spike protein gene coding for the S-antigen, which stimulates the immune response. CASE REPORT We describe an acute event of crystal arthritis after a carpal tunnel syndrome release followed by administration of the second dose of anti-COVID-19 Vaccine Oxford-AstraZeneca (ChAdOx1 nCoV-19). Medical treatment resulted in full resolution of the symptoms in 2 weeks. CONCLUSIONS Although most episodes of acute arthritis happen spontaneously, certain factors may trigger the acute CPP crystal arthritis such as intercurrent illnesses or surgeries. Although the association between carpal tunnel syndrome and CPP arthritis has been known for over 40 years, surgical release of the carpal ligament has always been associated with full resolution of symptoms. This is the first case report describing an exacerbation after carpal canal release, concomitant with the administration of the vaccine. According to our opinion, the vaccination associated with a prior surgery in the same anatomical site could have synergically triggered the arthritis flare-up, in a predisposed patient, with a mechanism still unknown.
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COVID-19 , Síndrome del Túnel Carpiano , Condrocalcinosis , Artropatías por Depósito de Cristales , Pirofosfato de Calcio/uso terapéutico , Síndrome del Túnel Carpiano/diagnóstico , Síndrome del Túnel Carpiano/etiología , Síndrome del Túnel Carpiano/cirugía , ChAdOx1 nCoV-19 , Condrocalcinosis/complicaciones , Condrocalcinosis/tratamiento farmacológico , Condrocalcinosis/metabolismo , Humanos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Vacunación/efectos adversos , MuñecaRESUMEN
OBJECTIVES: Microcrystal-induced arthritis is still an unresolved paradigm for medicine. Overt inflammation may be absent even when crystals occur in SF. Recently, the production of neutrophil extracellular traps (NETs) embedding MSU crystals has been proposed as a possible mechanism of the auto-resolution of the inflammatory phase during gout. We aimed to verify and quantify the release of NETs in SFs during gout and pseudogout attacks and to compare any differences with respect to crystals and neutrophils number, and to analyse activation of necroptosis pathway in SF from crystal-induced arthritis. METHODS: SF samples were obtained by arthrocentesis from 22 patients presenting acute crystal-induced arthritis, gout or pseudogout (n = 11 each group), and from 10 patients with acute non-crystal arthritis as controls. NETosis was quantified in SF by nucleic acid stain and by quantification of human neutrophil elastase. Activation of phosphorylated MLKL was assessed by western blot. RESULTS: We observed that SF neutrophils encountering MSU and CPPD crystals during episodes of gout and pseudogout release NETs in relation to the number of crystals in SF and irrespective of neutrophil density and type of crystal. This release was accompanied by necroptosis through the activation of the MLKL pathway. CONCLUSIONS: Our findings suggest that a role of NETs in crystal-induced arthritis is to 'trap extracellular particles', including microcrystals. Embedding crystals in aggregates of NETs may be the basis of tophi and CPPD deposition, and may have implications for disease evolution rather than for spontaneous resolution of the acute attack.
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Condrocalcinosis/patología , Trampas Extracelulares , Gota/patología , Recuento de Leucocitos , Western Blotting , Estudios de Casos y Controles , Condrocalcinosis/metabolismo , Citometría de Flujo , Gota/metabolismo , Humanos , Neutrófilos/patologíaRESUMEN
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.
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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
Calcium pyrophosphate dihydrate deposition (CPPD) disease, also known as pseudogout, in which crystals are deposited in the joints and/or soft tissues, leads to a variety of articular and periarticular disorders. Herein we report a 67-year-old female patient with neck pain who was diagnosed as CPPD disease of both the atlantoaxial joint and right C4-C5 facet joint with radiological findings. The combined use of computed tomography and magnetic resonance imaging can be helpful in establishing a diagnosis and providing the correct treatment.
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Articulación Atlantoaxoidea , Vértebras Cervicales , Condrocalcinosis , Dolor de Cuello , Articulación Cigapofisaria , Anciano , Articulación Atlantoaxoidea/diagnóstico por imagen , Articulación Atlantoaxoidea/patología , Pirofosfato de Calcio/análisis , Condrocalcinosis/diagnóstico , Condrocalcinosis/metabolismo , Condrocalcinosis/fisiopatología , Diagnóstico Diferencial , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Dolor de Cuello/diagnóstico , Dolor de Cuello/etiología , Tomografía Computarizada por Rayos X/métodos , Articulación Cigapofisaria/diagnóstico por imagen , Articulación Cigapofisaria/patologíaRESUMEN
ANKH mutations are associated with calcium pyrophosphate deposition disease and craniometaphyseal dysplasia. This study investigated the effects of these ANKH mutants on cellular localisation and associated biochemistry. We generated four ANKH overexpression-plasmids containing either calcium pyrophosphate deposition disease or craniometaphyseal dysplasia linked mutations: P5L, E490del and S375del, G389R. They were transfected into CH-8 articular chondrocytes and HEK293 cells. The ANKH mutants dynamic differential localisations were imaged and we investigated the interactions with the autophagy marker LC3. Extracellular inorganic pyrophosphate, mineralization, ENPP1 activity expression of ENPP1, TNAP and PIT-1 were measured. P5L delayed cell membrane localisation but once recruited into the membrane it increased extracellular inorganic pyrophosphate, mineralization, and ENPP1 activity. E490del remained mostly cytoplasmic, forming punctate co-localisations with LC3, increased mineralization, ENPP1 and ENPP1 activity with an initial but unsustained increase in TNAP and PIT-1. S375del trended to decrease extracellular inorganic pyrophosphate, increase mineralization. G389R delayed cell membrane localisation, trended to decrease extracellular inorganic pyrophosphate, increased mineralization and co-localised with LC3. Our results demonstrate a link between pathological localisation of ANKH mutants with different degrees in mineralization. Furthermore, mutant ANKH functions are related to synthesis of defective proteins, inorganic pyrophosphate transport, ENPP1 activity and expression of ENPP1, TNAP and PIT-1.
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Enfermedades del Desarrollo Óseo/genética , Condrocalcinosis/genética , Anomalías Craneofaciales/genética , Hiperostosis/genética , Hipertelorismo/genética , Mutación , Proteínas de Transporte de Fosfato/genética , Fosfatasa Alcalina , Autofagia , Enfermedades del Desarrollo Óseo/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Condrocalcinosis/metabolismo , Condrocitos/metabolismo , Anomalías Craneofaciales/metabolismo , Difosfatos/metabolismo , Células HEK293 , Humanos , Hiperostosis/metabolismo , Hipertelorismo/metabolismo , Microscopía Confocal , Proteínas de Transporte de Fosfato/metabolismo , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , Dominios Proteicos , Pirofosfatasas/genética , Pirofosfatasas/metabolismo , Factor de Transcripción Pit-1/genética , Factor de Transcripción Pit-1/metabolismoAsunto(s)
Condrocalcinosis/diagnóstico por imagen , Trastornos de la Articulación Temporomandibular/diagnóstico por imagen , Enfermedad Aguda , Anciano de 80 o más Años , Artralgia/fisiopatología , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Condrocalcinosis/metabolismo , Condrocalcinosis/patología , Condrocalcinosis/fisiopatología , Femenino , Fiebre/fisiopatología , Humanos , Dolor de Cuello/fisiopatología , Trastornos de la Articulación Temporomandibular/metabolismo , Trastornos de la Articulación Temporomandibular/patología , Trastornos de la Articulación Temporomandibular/fisiopatología , Tomografía Computarizada por Rayos X , Trismo/fisiopatologíaAsunto(s)
Vértebras Cervicales/diagnóstico por imagen , Condrocalcinosis/diagnóstico por imagen , Diagnóstico Diferencial , Apófisis Odontoides/diagnóstico por imagen , Osteomielitis/diagnóstico , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Condrocalcinosis/complicaciones , Condrocalcinosis/metabolismo , Humanos , Articulación de la Rodilla/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Dolor de Cuello/etiología , Osteomielitis/metabolismo , Radiografía , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Despite ground-breaking clinical success in the treatment of different cancers, immune checkpoint inhibitors can cause profound inflammatory and immune-related adverse events. Autoimmune inflammatory arthritis following immune checkpoint inhibitor treatment has been reported; however, to date, no cases of crystal arthritis following immune checkpoint inhibitors have been identified. CASE PRESENTATION: We report the first case of recurrent pseudogout, an inflammatory crystal arthritis, in a patient treated with nivolumab, a PD-1 inhibitor, for renal cell carcinoma. The patient had recurrent pseudogout flares about week to 10 days after each nivolumab infusion. After treatment with prophylactic colchicine, the patient well tolerated additional nivolumab infusions without adverse events. In parallel, we characterized immune cells of synovial fluid at each flare. Immunoprofiling of synovial fluid showed that the proportion of inflammatory IL-17-producing CD4+ T cells and amount of IL-17 were notably increased in synovial fluid with every recurrent flair, and correlated with the increase in number of synovial neutrophils, suggesting a potential role of T helper 17 (Th17) cells in neutrophil-driven inflammation during pseudogout arthritis. CONCLUSIONS: This case suggests a potential influence of Th17 cells on the neutrophil recruitment and neutrophil-driven inflammatory events leading to pseudogout induced by immune checkpoint inhibitor therapy.
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Antineoplásicos Inmunológicos/efectos adversos , Condrocalcinosis/diagnóstico , Condrocalcinosis/etiología , Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos B/inmunología , Linfocitos B/metabolismo , Biomarcadores , Carcinoma de Células Renales/complicaciones , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/tratamiento farmacológico , Condrocalcinosis/metabolismo , Citocinas/metabolismo , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Nivolumab/efectos adversos , Nivolumab/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Recurrencia , Líquido Sinovial/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
INTRODUCTION: Chondrocalcinosis results from calcium pyrophosphate crystals deposition in the joints. We report an exceptional case of aseptic psoas abscess with a deposition of calcium pyrophosphate crystals. CASE REPORT: A 92-year-old man presented to our department for an acute onset of inflammatory pain in the left hip. Computed tomography detected a coxofemoral arthritis and multiple intramuscular collections located in the iliopsoas muscle and the gluteus minimus. A sample of the fluid was obtained with a guided aspiration, and its analysis revealed an inflammatory liquid with no bacteria but numerous calcium pyrophosphate crystals. The final diagnosis was thus a muscular calcium pyrophosphate deposition pseudo-abscess, associated with a hip arthritis. CONCLUSION: Hip chondrocalcinosis is unusual, and the association with intramuscular deposition of calcium pyrophosphate crystals seems extremely rare as we found only four other published cases. A microcrystalline arthritis could have spread from the coxofemoral joint through the iliopsoas bursa and into the muscle. However, the imaging aspect with an abscess and a predominant muscular injury might suggest a mechanism of crystal formation originating directly within the muscle. The outcome was always favourable even if some patients required surgery.
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Absceso/diagnóstico , Pirofosfato de Calcio/metabolismo , Condrocalcinosis/diagnóstico , Miositis/diagnóstico , Absceso/metabolismo , Absceso/patología , Anciano de 80 o más Años , Condrocalcinosis/metabolismo , Condrocalcinosis/patología , Diagnóstico Diferencial , Cadera , Humanos , Masculino , Miositis/metabolismo , Miositis/patologíaRESUMEN
OBJECTIVE: To preliminarily explore the diagnostic potential of ultrasound (US) in detecting calcium pyrophosphate (CPP) crystal deposits at the hip joint in a cohort of patients with CPP deposition disease (CPPD) who were previously evaluated by conventional radiography (CR) and to assess the sensitivity and specificity as well as the agreement between US and CR in the evaluation of hip CPP crystal deposits. METHODS: Fifty consecutive patients with definite CPPD and 40 age/sex/body mass index-matched disease control subjects who had undergone hip CR within the previous 6 months were enrolled. Bilateral hip US examination was carried out to assess the presence of CCP crystal deposits at the acetabular labrum fibrocartilage and at the femoral head's hyaline cartilage. Two independent radiologists evaluated the presence of hip CPP crystal deposits on CR in both groups. RESULTS: US findings indicative of CPP crystal deposits were found in at least 1 hip in 45 of 50 patients with CPPD (90.0%) and in 73 of 100 hips (73.0%). CPP crystal deposits were more frequently found at the acetabular labrum fibrocartilage than at the femoral head's hyaline cartilage (72% and 17% of the hips in patients with CPPD, respectively). US and CR sensitivity was 90% and 86%, whereas US and CR specificity was 85% and 90%, respectively. Total agreement between the US and CR findings was 77.8%. CONCLUSION: Our results provide new evidence supporting US as a first-line, sensitive, safe, and reliable imaging technique in detecting CPP crystal deposits at the hip level.
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Pirofosfato de Calcio/metabolismo , Cartílago Articular/diagnóstico por imagen , Condrocalcinosis/diagnóstico , Articulación de la Cadera/diagnóstico por imagen , Ultrasonografía/métodos , Anciano , Condrocalcinosis/metabolismo , Femenino , Articulación de la Cadera/metabolismo , Humanos , Masculino , Sistema Musculoesquelético/diagnóstico por imagen , Curva ROC , Radiografía/métodos , Reproducibilidad de los ResultadosRESUMEN
We report a case of calcium pyrophosphate deposition disease (CPPD) with an unusual presentation of severe chondrocalcinosis with atypical large burden deposited in the metacarpophalangeal joints as well as more typical deposition in wrists and knees as demonstrated on plain radiographs. A 77-year-old African-American woman 1-year status post parathyroidectomy for hyperparathyroidism initially presented to the rheumatology clinic to treat suspected rheumatoid arthritis given her pattern of joint involvement but was found to have CPPD. The patient's history is notable for end-stage renal disease which complicates medical management. This case illustrates radiographic findings of CPPD and explores the challenges of treating CPPD in the setting of comorbid conditions.
Asunto(s)
Artralgia/etiología , Pirofosfato de Calcio/metabolismo , Condrocalcinosis/complicaciones , Articulación Metacarpofalángica , Anciano , Articulación del Tobillo/diagnóstico por imagen , Antiinflamatorios/uso terapéutico , Condrocalcinosis/diagnóstico , Condrocalcinosis/tratamiento farmacológico , Condrocalcinosis/metabolismo , Diagnóstico Diferencial , Femenino , Humanos , Articulación de la Rodilla/diagnóstico por imagen , Articulación Metacarpofalángica/diagnóstico por imagen , Prednisona/uso terapéuticoRESUMEN
Objectives: Calcium pyrophosphate deposition (CPPD) is associated with osteoarthritis and is the cause of a common inflammatory articular disease. Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (eNPP1) is the major ecto-pyrophosphatase in chondrocytes and cartilage-derived matrix vesicles (MVs). Thus, eNPP1 is a principle contributor to extracellular pyrophosphate levels and a potential target for interventions aimed at preventing CPPD. Recently, we synthesized and described a novel eNPP1-specific inhibitor, SK4A, and we set out to evaluate whether this inhibitor attenuates nucleotide pyrophosphatase activity in human OA cartilage. Methods: Cartilage tissue, chondrocytes and cartilage-derived MVs were obtained from donors with OA undergoing arthroplasty. The effect of SK4A on cell viability was assayed by the XTT method. eNPP1 expression was evaluated by western blot. Nucleotide pyrophosphatase activity was measured by a colorimetric assay and by HPLC analysis of adenosine triphosphate (ATP) levels. ATP-induced calcium deposition in cultured chondrocytes was visualized and quantified with Alizarin red S staining. Results: OA chondrocytes expressed eNPP1 in early passages, but this expression was subsequently lost upon further passaging. Similarly, significant nucleotide pyrophosphatase activity was only detected in early-passage chondrocytes. The eNPP1 inhibitor, SK4A, was not toxic to chondrocytes and stable in culture medium and human plasma. SK4A effectively inhibited nucleotide pyrophosphatase activity in whole cartilage tissue, in chondrocytes and in cartilage-derived MVs and reduced ATP-induced CPPD. Conclusion: Nucleotide analogues such as SK4A may be developed as potent and specific inhibitors of eNPP1 for the purpose of lowering extracellular pyrophosphate levels in human cartilage with the aim of preventing and treating CPPD disease.
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Calcinosis/tratamiento farmacológico , Pirofosfato de Calcio/metabolismo , Condrocalcinosis/tratamiento farmacológico , Condrocitos/patología , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/farmacología , Pirofosfatasas/antagonistas & inhibidores , Calcinosis/metabolismo , Calcinosis/patología , Células Cultivadas , Condrocalcinosis/metabolismo , Condrocalcinosis/patología , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Colorimetría , Humanos , Immunoblotting , Hidrolasas Diéster Fosfóricas/biosíntesis , Pirofosfatasas/biosíntesisRESUMEN
PURPOSE OF REVIEW: Calcium crystals exist in both pathological and normal articular cartilage. The prevalence of these crystals dramatically increases with age, and crystals are typically found in osteoarthritic cartilage and synovial fluid. Relatively few studies have examined the effects of crystals on cartilage biomechanics or chondrocyte mechanotransduction. The purpose of this review is to describe how crystals could influence cartilage biomechanics and mechanotransduction in osteoarthritis. RECENT FINDINGS: Crystals are found in both loaded and unloaded regions of articular cartilage. Exogenous crystals, in combination with joint motion, result in substantial joint inflammation. Articular cartilage vesicles promote crystal formation, and these vesicles are found near the periphery of chondrocytes. Crystallographic studies report monoclinic symmetry for synthetic crystals, suggesting that crystals will have a large stiffness compared with the cartilage extracellular matrix, the pericellular matrix, or the chondrocyte. This stiffness imbalance may cause crystal-induced dysregulation of chondrocyte mechanotransduction promoting both aging and osteoarthritis chondrocyte phenotypes. SUMMARY: Because of their high stiffness compared with cartilage matrix, crystals likely alter chondrocyte mechanotransduction, and high concentrations of crystals within cartilage may alter macroscale biomechanics. Future studies should focus on understanding the mechanical properties of joint crystals and developing methods to understand how crystals affect chondrocyte mechanotransduction.
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Fosfatos de Calcio/metabolismo , Pirofosfato de Calcio/metabolismo , Cartílago Articular/metabolismo , Condrocalcinosis/metabolismo , Condrocitos/metabolismo , Matriz Extracelular/metabolismo , Osteoartritis/metabolismo , Cartílago Articular/citología , Cartílago Articular/fisiopatología , Condrocalcinosis/fisiopatología , Condrocitos/citología , Humanos , Mecanotransducción Celular/fisiología , Osteoartritis/fisiopatología , Estrés Mecánico , Soporte de PesoRESUMEN
The protein product of the progressive ankylosis gene, known as ANK, is a 492-amino acid multi-pass transmembrane protein. This protein is critical for the regulation of pyrophosphate, and gain of function ANK mutations is associated with calcium pyrophosphate deposition disease. Much about the structure, function, and regulation of ANK remain unstudied. This review of the current literature examines recent contributions to our understanding of ANK. We focus on new work on the function, binding partners, and regulators of ANK. A more complete understanding of this important protein may help to identify future therapeutic targets for the treatment of calcium pyrophosphate deposition disease.
Asunto(s)
Condrocalcinosis/metabolismo , Proteínas de Transporte de Fosfato/metabolismo , Condrocalcinosis/genética , Humanos , Mutación , Proteínas de Transporte de Fosfato/genética , Conformación ProteicaRESUMEN
Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease rarely occurs in the posterior aspect of the craniocervical junction (CCJ). To the best of our knowledge, there have been only 2 previously reported cases of patients with posterior CPPD lesions in this region that have led to cervical myelopathy. We report the case of a 70-year-old man presenting with neck pain and cervical myelopathy with multilevel stenosis from C1-C6. The stenosis was worst at C1-C2, secondary to compression by a CPPD lesion posterior to the spinal cord. The patient underwent a C2-C6 laminectomy and fusion with resection of the CPPD lesion. In this report, we discuss the patient and present a novel theory to explain the preponderance of CPPD lesions in the CCJ occurring anteriorly and not posteriorly to the spinal cord.
Asunto(s)
Pirofosfato de Calcio/metabolismo , Vértebras Cervicales , Condrocalcinosis/patología , Ligamentos/patología , Compresión de la Médula Espinal/etiología , Médula Espinal/patología , Anciano , Condrocalcinosis/metabolismo , Artropatías por Depósito de Cristales , Humanos , Laminectomía , Ligamentos/metabolismo , Masculino , Dolor de Cuello/diagnóstico , Dolor de Cuello/etiología , Compresión de la Médula Espinal/diagnóstico , Estenosis EspinalRESUMEN
PURPOSE OF REVIEW: Calcium pyrophosphate (CPP) crystal disease is a common rheumatologic disorder that has received limited attention from the scientific community. This review is aimed at summarizing current evidence for managing CPP disease (CPPD), focusing on recently reported advances. RECENT FINDINGS: New data from case series indicate that interleukin-1ß inhibitors can help patients with refractory forms of CPPD. Methotrexate, formerly a promising agent, failed to demonstrate benefits in a recent trial, but still merits consideration for some patients. No significant advances on crystal dissolution have been achieved to date. Proper characterization of the CPP crystal disease picture is needed, ruling out the possible coexistence of another persistent arthritis unrelated to the CPP deposition. SUMMARY: Advances on CPP crystal dissolution and establishing definitions of the clinical spectrum of CPPD remain the main challenges for CPP crystal disease management.