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PubMed1992

Synovial, articular cartilage and bone changes in rapidly destructive arthropathy (osteoarthritis) of the hip.

We studied ten femoral heads from eight patients suffering from rapidly destructive arthropathy (RDA) of the hip. At surgery, 1-3.5 ml of synovial fluid, ranging from citrous to hemorrhagic, was aspirated from six joints. This fluid was viscous, pauci-cellular and did not contain calcium pyrophosphate dihydrate (CaPPD) crystals, although significant amounts of alizarin S-positive material was found in three joints. Significant synovial hyperplasia was found in four joints and moderate hyperplasia in two. Synovium was hypertrophic, hypercellular and slightly to moderately fibrotic. It lacked evidence of perivascular inflammatory infiltrates. Synovium often contained amyloid micro-deposits and alizarin S-positive osteocartilagenous debris surrounded by macrophages. Synovial hyperplasia had a good correlation with osteocartilagenous debris and a poor correlation with amyloid infiltration. Femoral heads were usually flattened and exhibited large areas of exposed bone spotted by plugs of fibro-cartilagenous tissue. Subchondral bone contained large ischemic and necrotic areas, bone marrow atrophy and fibrosis, and intense bone remodeling. Subchondral bone necrosis and ischemia were the most significant findings of this study and their role in the development of RDA is discussed.

Aged↗

PubMed1977

[Cartilage of the head of the femoral in articular chondrocalcinosis (author's transl)].

A study of three femoral heads removed from patients suffering from articular chondrocalcinosis enabled the authors to identify the lesions of the cartilage in that disorder. They are mainly represented by crystals of calcium pyrophosphate. They appear within the cartilage which is macroscopically intact and histologically normal, but their location and the related tissue phenomena in their formation remain controversial and poorly understood. They accumulate in the various layers of the non-calcified cartilage within which they appear to hollow out genuine cavities by pushing back and then destroying the intercellular matrix and surrounding chondrocytes. In spite of their at times considerable size, the accumulations of crystals are not accompanied with fissures or erosion of cartilage tissue. This good histological tolerance appears to be explained by the distribution of calcification outside of the areas bearing pressure, which is in agreement with the often asymptomatic nature of chondrocalcinosis. These calcfications appear to be able to render cartilage fragile and to lead to pseudoarthrosic arthropathy when they are abundant and spread through the entire surface of a joint.

Aged↗

PubMed1987

[Alizarin red staining of articular fluids. Comparison of the results with electron microscopy and clinical data].

Coloration of articular fluids with alizarin S red has been proposed as a method of sensitive detection of calcium microcrystals, especially apatite crystals. We are reporting the results of a study of 230 non-selected fluids. The results of the coloration were quantified into negative, slightly positive, moderately positive and strongly positive. Study of X-Rays of the tapped joint and of the hospital file was done in 199 patients. Electron microscope study, of 44 fluid samples, shows that the coloration with alizarin red permits a reliable detection of calcium microcrystals in the articular fluid, only if the strongly positive results are taken into account. But the coloration is not specific for apatite: 5 strongly positive fluids out of 14 contain only, in electron microscopy, crystals of dihydrated calcium pyrophosphate. 10.8% of the stained fluids give a strongly positive result. In two cases, it concerns destructive arthropathies of the shoulder with periarticular calcifications. The other strongly positive results are found in chondrocalcinosis (52 p. cent), in arthrosis (17 p. cent) and in rheumatoid polyarthritis (15 p. cent). As a whole, the results are correlated with age and the degree of radiological destruction. The similar percentage of strongly positive fluids observed in arthrosis and rheumatoid polyarthritis, is not in favor of a specific role of apatite microcrystals in the pathogenesis of arthrosis. Since the majority of strongly positive fluids come from joints which are very destroyed, regardless of the arthropathy concerned (rheumatoid polyarthritis, chondrocalcinosis or arthrosis), it is possible to think that it is mostly the destruction of the sub-chondral bone which explains these results.

Anthraquinones↗

PubMed1989

Is it mandatory to examine synovial fluids promptly after arthrocentesis?

Fifty synovial fluid (SF) samples from patients with various types of arthritis were examined promptly after joint aspiration and after storage at room temperature (22 degrees C) or at refrigerator temperature (4 degrees C) for 1 hour, 2 hours, 3 hours, 6 hours, 1 day, and 3 days, then weekly for 3 weeks and monthly for 2 months. We found that the leukocyte count (white blood cell [WBC] count) decreased within a few hours. In 4 SF samples from patients with mild inflammation (initial range 3,150-6,200 WBC/mm3), the WBC count decreased into a "noninflammatory" range (less than 2,000/mm3) within 5-6 hours. In 3 of 5 SF samples that on the first day were found to be laden with crystals of calcium pyrophosphate dihydrate (CPPD), the crystals were much less abundant and were difficult to recognize by the next day. CPPD crystals dissolved completely in all SF samples by 3-8 weeks of the study. Monosodium urate crystals remained detectable throughout the 8 weeks of study, but they became smaller, less birefringent, and less numerous with time. Clumps of apatite-like crystals persisted for several months. Most SF samples initially negative for apatite-like crystals remained negative over time. New, artifactual crystals, including alizarin red S-positive clumps or star-shaped arrays, plate-like structures, positively birefringent Maltese crosses, and hematoidin crystals, developed with time. Because of these observations, we urge prompt examination of SF specimens to avoid the problems of misdiagnosing borderline inflammatory fluids, missing CPPD crystals that dissolve with time, or over-interpreting the findings because of the new, artifactual crystals.

Apatites↗

PubMed2000

The involvement of phospholipase C in crystal induced human neutrophil activation.

OBJECTIVE: To investigate the involvement of phospholipase C (PLC) in the signal transduction pathway leading to neutrophil activation by inflammatory microcrystals. METHODS: Neutrophil chemiluminescence, superoxide anion generation, and degranulation responses to opsonized crystals were measured in the presence of U73122, a specific inhibitor of PLC. Phospholipase Cgamma2 (PLCgamma2) activity was measured by Western blotting. RESULTS: U73122 was shown to inhibit neutrophil activation induced by plasma opsonized crystals of calcium pyrophosphate dihydrate (CPPD) and monosodium urate monohydrate. The IC50 for inhibition of crystal induced respiratory burst (measured by chemiluminescence) was roughly 3 microM. No inhibition of crystal induced respiratory burst was observed using U73343, an inactive analog of U73122. These results show the pivotal role of PLC in neutrophil respiratory burst activation by both crystals. Superoxide anion generation and degranulation responses of neutrophils to CPPD crystals were also strongly inhibited by U73122 at a concentration of 10 microM, supporting the concept of direct involvement of PLC in signal transduction pathways leading to crystal induced oxidase activation and degranulation responses. CPPD crystals caused a sustained increase in the tyrosine phosphorylation levels of PLCgamma2 in neutrophils. CONCLUSION: We conclude that PLC plays a central role in signal transduction pathways leading to respiratory burst and degranulation responses in neutrophils activated by inflammatory microcrystals, and that PLCgamma2 may be the isoform involved in these pathways.

Calcium↗

PubMed1985

Bradykinin levels in inflammatory exudates.

An enzyme immunoassay was used to measure the levels of bradykinin (BK)-like immunoreactivity in inflammatory exudates provoked by calcium pyrophosphate (CaPP) or carrageenin. BK-like immunoreactivity increased from 4 to 18 ng/ml in exudates provoked by CaPP and collected from 30 min to 3 h after induction of pleurisy. BK levels decreased progressively (from 16 to 3 ng/ml) in the samples collected at 4 and 6 h. BK levels did not increase in exudates provoked by carrageenin. Control samples of exudates provoked by CaPP but not treated with peptidase inhibitors [orthophenanthroline (OPH) or a mixture of EDTA-captopril-thioglycolic acid (ECT)] as well as samples containing one or the other peptidase inhibitors dissolved in saline, were also negative. The present results indicate that an increased production of kinins is detectable only in exudates induced by CaPP and not in those provoked by carrageenin. Our data also suggest that the kinins are rapidly metabolized, both in vitro (in the exudate sample) and in vivo (in the rat pleural cavity).

Animals↗

PubMed1985

The modification of the oxidative metabolism of cells derived both locally and at distance from the site of an acute inflammatory reaction.

During an acute nonspecific inflammatory reaction initiated in the pleural cavity by a nondiffusible stimulus (calcium pyrophosphate crystals), the oxidative metabolism, as measured by chemiluminescence and superoxide release, of cells harvested from both the inflammatory site and at points distant from it was studied. The oxidative metabolism of peritoneal macrophages, obtained from rats undergoing an inflammatory reaction (pleurisy), demonstrated a transient decrease in activity compared with the resident population when using both zymosan and phorbol myristate acetate as stimulants. This metabolic unresponsiveness induced by inflammation may be related to the concomitant changes in the levels of prostacyclin in the peritoneal cavity. It should be emphasized that the peritoneal cellular composition or number did not change during these events. On the other hand alveolar macrophages from inflamed animals showed no significant changes in their superoxide production or chemiluminescence compared to controls. The precise reason for these inflammation-induced changes is unknown; however the acute nonspecific inflammatory reaction was able to modulate the oxidative metabolism of cells not only at the site of inflammation, but at points distant from it.

Acute Disease↗

PubMed1996

Paradoxical effects of colchicine on the activation of human neutrophilis by chemotactic factors and inflammatory microcrystal.

Neutrophil activation by chemotactic factors and by inflammatory microcrystals is accompanied by increases in protein tyrosine phosphorylation and by the activation of the NADPH oxidase. The addition of colchicine inhibited both responses induced by triclinic monosodium urate or calcium pyrophosphate crystals. On the other hand, colchicine enhanced the tyrosine phosphorylation of specific protein in neutrophils stimulated by chemotactic factor and augmented the production of superoxide anions induced by these same agonists. The effects of colchicine were shared by other anti-microtubule agents (nocodazole and vinblastine) but not by its inactive analogue beta-lumicolchicine, trimethylcolchicinic acid, indomethacin, or phenylbutazone. Furthermore, the (enhancing as well as inhibitory) effects of colchicine on tyrosine phosphorylation and superoxide anion production were reversed by taxol. Finally, in human cytoplasts colchicine again inhibited microcrystal-stimulated tyrosine phosphorylation but did not change chemotactic factor-stimulated phosphorylation. These data strongly support the hypothesis that microtubule-related mechanisms are involved in the modulation of the tyrosine phosphorylation response in human neutrophils, and suggest that a relationship may exist between the augmentation of tyrosine phosphorylation and of the stimulation of the NADPH oxidase induced by chemotactic factors.

Adult↗

PubMed2001

The structures of Escherichia coli inorganic pyrophosphatase complexed with Ca(2+) or CaPP(i) at atomic resolution and their mechanistic implications.

Two structures of Escherichia coli soluble inorganic pyrophosphatase (EPPase) complexed with calcium pyrophosphate (CaPP(i)-EPPase) and with Ca(2+) (Ca(2+)-EPPase) have been solved at 1.2 and 1.1 A resolution, respectively. In the presence of Mg(2+), this enzyme cleaves pyrophosphate (PP(i)) into two molecules of orthophosphate (P(i)). This work has enabled us to locate PP(i) in the active site of the inorganic pyrophosphatases family in the presence of Ca(2+), which is an inhibitor of EPPase.Upon PP(i) binding, two Ca(2+) at M1 and M2 subsites move closer together and one of the liganded water molecules becomes bridging. The mutual location of PP(i) and the bridging water molecule in the presence of inhibitor cation is catalytically incompetent. To make a favourable PP(i) attack by this water molecule, modelling of a possible hydrolysable conformation of PP(i) in the CaPP(i)-EPPase active site has been performed. The reasons for Ca(2+) being the strong PPase inhibitor and the role in catalysis of each of four metal ions are the mechanistic aspects discussed on the basis of the structures described.

Binding Sites↗

PubMed1990

The distribution of calcific deposits in intervertebral discs of the lumbosacral spine.

The incidence of intervertebral disc calcifications (IVDCs) was examined in 52 lumbosacral spines obtained sequentially at autopsy. The presence of calcific deposits was detected by fine-grain roentgenograms. The nature of these deposits was determined by wide-angle x-ray diffraction, and histologic observations were made. A high prevalence of IVDC, 18 spines of 52, some with multiple deposits, was noted. Calcium pyrophosphate dihydrate (CPPD) deposits were found in 3% of the spines and accounted for 29% of the 42 deposits analyzed. The CPPD deposits occurred at multiple disc levels (an average of four per spine), were diffuse, and involved a major portion of the disc (nucleus pulposus, annulus fibrosus, and endplate) but were not generally associated with histologic disc degeneration. Hydroxyapatite (HA) deposits occurred in 12% of the spines, most often in the nucleus pulposus and endplate. The HA deposits appeared as small punctate radiodensities. Roentgenographic evidence of degenerative changes, i.e., disc space narrowing, endplate disruption, desiccation, and osteophyte formation, were present in all but one of the spines containing HA deposits. An additional 19% of the spines had deposits that could not be characterized by x-ray diffraction but were very similar in roentgenographic appearance to HA deposits. No conclusions could be drawn on the relationship between the presence of HA or CPPD and collagen or hexosamine content.

Adult↗

PubMed2006

Gout-associated uric acid crystals activate the NALP3 inflammasome.

Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues. Although MSU crystals were first identified as the aetiological agent of gout in the eighteenth century and more recently as a 'danger signal' released from dying cells, little is known about the molecular mechanisms underlying MSU- or CPPD-induced inflammation. Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1beta and IL-18. Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1beta activation. Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1beta receptor (IL-1R). These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.

Animals↗

PubMed1980

Crystal-associated arthropathies: what's new in old joints.

Degenerative arthritis in the aged includes two major disease categories--osteoarthritis and the crystal-associated arthropathics. The crystals chiefly involved are monosodium urate (gout) and calcium pyrophosphate dihydrate (CPPD), although several others (e.g., cholesterol, brushite and apatite) have been implicated. This report illustrates how the newer diagnostic techniques such as polarized-light microscopy, analytical electron microscopy and x-ray microdiffraction have augmented knowledge concerning diseases associated with articular crystal deposition. For example, diffraction techniques are required for accurate identification of the apatite crystals found in synovial fluid effusions and in the matrix vesicles of degenerate cartilage. According to ultrastructural studies, monosodium urate crystals found in tophi, joint surfaces and effusions show a distinct morphology. Present in inactive joints, the crystal surfaces are bare; in acute gout, the crystals are covered with mucin, confirming the observation that protein binding to crystals is necessary for inflammation to proceed. CPPD disease is by far the most common crystal-associated arthropathy affeting the aged. The incidence of CPPD deposits in articular tissues increases with age but, in contrast to gout, affects both men and women. The pathogenesis of CPPD disease is a mystery, but factors under investigation include matrix abnormalities, ionic imbalances, and enzyme disorders.

Aged↗

PubMed1983

Crystal deposition disease.

Calcium pyrophosphate dihydrate crystal deposition disease and HA crystal deposition disease are two common disorders that may come to the attention of a physician because of a variety of clinical symptomatology patterns. In CPPD crystal deposition disease, characteristic radiologic features include articular and periarticular calcification and an arthropathy consisting of joint space narrowing, bone sclerosis, often prominent subchondral cyst formation, occasional severe and progressive destructive bone changes, and variable osteophyte formation. These findings are often seen in a characteristic distribution with involvement of non-weight-bearing as well as weight-bearing joints and with involvement of distinctive intraarticular sites such as the patellofemoral compartment of the knee and the radiocarpal compartment of the wrist. In HA crystal deposition disease, characteristic radiologic features consist of calcific tendinitis and periarthritis as well as a more recently described arthropathy. Awareness of the distinctive roentgenographic appearance of these two diseases should allow a specific diagnosis to be made, and an understanding of their pathologic features should aid in appropriate therapy and guide future investigation of possible etiologic factors.

Aged↗

PubMed2003

[Crowned dens syndrome: three new cases].

INTRODUCTION: Crowned dens syndrome is due to a microcrystalline infringement (hydroxyapatite or calcium pyrophosphate) of the retro-odontoidal ligament of atlas, often leading to the erroneous diagnosis of meningitis or spondylitis. We report on three new cases diagnosed from 1996 to 1999. EXEGESIS: The patients complained of cervicalgies, headaches or fever. The initially evoked diagnoses were meningitis, spondylodiscitis or endocarditis. Clinical exam found meningism and an inflammatory syndrome in all patients. Analysis of the cerebro-spinal fluid realised in two cases was normal. The diagnosis of crowned dens syndrome was assessed in two cases by cervical CT scan of C1/C2. In the third case, chondrocalcinosis of a wrist allowed this diagnosis. We report a probably non fortuitous case of crowned dens syndrome associated with genetic hemochromatosis. A non steroidal anti-inflammatory treatment allowed a dramatic regression of clinical symptoms. CONCLUSION: This entity should be better known; it can mimick numerous diagnosis and be responsible for fever in the long course.

Aged↗

PubMed2001

Inflammatory microcrystals induce murine macrophage survival and DNA synthesis.

The interaction of particulates with resident macrophages is a consistent feature in certain forms of crystal-induced inflammation, for example, in synovial tissues, lung, and the peritoneum. The mitogenic activity of basic calcium phosphate (BCP) crystals and calcium pyrophosphate dihydrate (CPPD) crystals on synovial fibroblasts has been considered relevant to the synovial hyperplasia observed in crystal-induced arthritis. The aim of the study was to determine whether microcrystals such as these could enhance macrophage survival and induce DNA synthesis, thus indicating that they may contribute to the tissue hyperplasia. Murine bone-marrow-derived macrophages were treated in vitro with microcrystals, the cell numbers were monitored over time, and DNA synthesis was measured as the incorporation of [methyl-(3)H]thymidine (TdR). We report here that BCP, monosodium urate, talc, and, to a lesser extent, CPPD crystals promote macrophage survival and DNA synthesis; the latter response is particularly striking in the presence of low concentrations of macrophage-colony stimulating factor (M-CSF, CSF-1). Enhanced macrophage survival or proliferation may contribute to the synovial hyperplasia noted in crystal-associated arthropathies, as well as to talc-induced inflammation and granuloma formation. The crystals studied join the list of particulates having these effects on macrophages, indicating the generality of this type of response.

Animals↗

PubMed1985

Crystal-induced endogenous pyrogen production. A further look at gouty inflammation.

We found previously that crystals of sodium urate and silicon dioxide (silica) can stimulate the production of endogenous pyrogen (EP), now called interleukin-1 (IL-1), the polypeptide mediator of fever and other aspects of inflammation. We have confirmed and extended the work with urate crystals and have examined 2 other crystals associated with joint problems, hydroxyapatite (HA) and calcium pyrophosphate dihydrate (CPPD). The crystals were added to suspensions of human blood leukocytes (2.5 X 10(6) monocytes/dose, with 10% fresh autologous plasma); after 18 hours of incubation, the EP content of the supernatants was assayed in the rabbit pyrogen test. HA and CPPD crystals neither induced EP production nor reduced the amount of staphylococci-induced EP. Presized (10 - 40 micron) urate crystals were pyrogenic, but less so than the unsized and aggregated urate crystals investigated previously and reexamined here. On ultrasonication, the aggregated urate crystals became first more pyrogenic and then less so as the crystals were dispersed and broken down. Ultrasound did not impart pyrogenicity to HA or CPPD crystals: their failure to stimulate EP/IL-1 production from leukocytes in vitro indicates a difference in their phlogistic properties, compared with crystals of urate or silica. The results with urate crystals have pathogenetic implications in a number of areas of gouty inflammation: initiation of the acute attack, other aspects of the acute-phase response, polyarticular involvement, and the inflammatory consequences of chronic stimulation by tophaceous material.

Calcium Pyrophosphate↗

PubMed1997

The involvement of phosphatidylinositol 3-kinase in crystal induced human neutrophil activation.

OBJECTIVE: We investigated whether phosphatidylinositol (PI) 3-kinase is involved in the signal transduction pathway leading to neutrophil activation by inflammatory microcrystals. METHODS: Neutrophil chemiluminescence and degranulation responses to opsonized crystals were measured in the presence of selective inhibitors known to inhibit PI 3-kinase activity in neutrophils. RESULTS: Wortmannin and LY 294002, 2 selective inhibitors of PI 3-kinase, were shown to inhibit neutrophil activation induced by plasma opsonized crystals of calcium pyrophosphate dihydrate (CPPD) [both monoclinic (M) and triclinic (T) forms] and monosodium urate monohydrate (MSUM). IC50 for wortmannin or LY 294002 inhibition of crystal induced respiratory burst (measured by chemiluminescence) was about 3 nM and 0.3 microM, respectively, proving the pivotal role of PI 3-kinase in neutrophil respiratory burst activation by all 3 crystals. Degranulation responses of neutrophils to CPPD(M) and CPPD(T) crystals were also inhibited by about 50% by wortmannin in the 10 to 20 nM concentration range, supporting the direct involvement of PI 3-kinase in signal transduction pathways leading to crystal induced neutrophil degranulation. All 3 crystals induced the activation of PI 3-kinase in neutrophils as measured by the increased PI 3-kinase activity associated with immunoprecipitated tyrosine phosphorylated proteins from 1 min crystal-neutrophil incubations. Neutrophils pretreated with wortmannin at 10 nM showed sub-basal levels of PI 3-kinase activity at all time points measured. CONCLUSION: PI 3-kinase plays a central role in the signal transduction pathways leading to respiratory burst and degranulation responses in neutrophils activated by inflammatory microcrystals.

Androstadienes↗

PubMed2002

Delayed examination of synovial fluid by ordinary and polarised light microscopy to detect and identify crystals.

OBJECTIVE: To determine the reliability of a delay in the microscopic examination of synovial fluid (SF) to detect and identify crystals. METHODS: Ninety one SF samples were examined, 31 with monosodium urate (MSU) crystals, 30 with crystals of calcium pyrophosphate dihydrate (CPPD), and 30 containing no crystals. The specimens were stored with EDTA, sodium heparin, and without anticoagulant at 4 degrees C before examination at 24 and 72 hours with ordinary and polarised light microscopy. Another aliquot of the same samples was stored in a plastic container without anticoagulant at -80 degrees C and examined after two months. RESULTS: When the samples stored at 4 degrees C were re-examined after 24 hours, intracellular crystals of MSU were seen in 90/93 (97%) cases where they had been identified previously and 89/93 (96%) cases after 72 hours. Similarly, CPPD crystals were identified in 90/90 (100%) and 87/90 (97%) cases after 24 and 72 hours. Examination of the samples stored at -80 degrees C showed intracellular MSU crystals in 25/31 (81%) of cases and CPPD crystals in 25/30 (83%). No crystals were seen in any sample which had previously been diagnosed as crystal-free. CONCLUSIONS: Deferred microscopic examination of refrigerated or deep frozen SF provides a strong probability of detecting MSU or CPPD crystals if these are present initially.

Calcium Pyrophosphate↗