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Calcium pyrophosphate deposition disease: description in defleshed skeletons.

The osseous appearance, skeletal distribution, and distinguishing features of calcium pyrophosphate deposition disease (CPPD) were delineated in a population of 2906 contemporary defleshed skeletons. The limitations of routine x-ray and clinical examination were transcended in this study of defleshed bones. The nature of the disease was clearly identified and preconceived notions (based on the "shades of black and white" of the conventional x-ray technique) were examined on the basis of the actual osseous impact. Epidemiologic assessment of this disease allowed it to be distinguished from rheumatoid and other erosive forms of arthritis. Analysis of the "pseudo-rheumatoid" subgroup of CPPD provided clear criteria for distinguishing the disease from rheumatoid arthritis. Characterization of the nature and epidemiology of osseous alterations in a contemporary skeletal population permitted the development of a standard for recognition of CPPD in skeletal populations and for clarification of the nature of associated pseudo-erosions.

Arthritis↗

[Scanning electron microscopic observations of calcium pyrophosphate crystals of joint tissues and synovial fluid (author's transl)].

The deposition and ultrastructure of calcium pyrophosphate (CPPD) crystals in joint tissues of pseudogout patients and cadavers were studied. Nine calcified menisci, 2 articular cartilages and 6 samples of synovial fluid were examined by scanning electron microscopy (SEM). Some of them were examined by analytical electron microscopy (EMMA). In the samples of menisci and cartilages, the findings were compared with those in the soft X-ray examinations and polarized light microscopy. The results are summarized as follows: 1) SEM observation of the cut surfaces of calcified menisci and cartilages showed a three-dimensional ultrastructure for the CPPD crystals. The crystals in the synovial fluid taken from pseudogout knees were also clearly demonstrated by this method. The EMMA analysis provided the possibility to examine the structure and content of the crystals simultaneously. 2) Crystal deposition in the meniscus varied with the depth of the tissues; it was diffuse in the collagen framework of the superficial layer, but showed accumulation in the deep layer where a clear line of demarcation between the collagen framework and crystals was seen. 3) The crystals in the meniscus were rod, granular or rectangular in shape, and 0.2-6.5 micro by 0.2-3.5 micro in size. Crystals from the articular cartilage were granular or rod-like in shape, and 0.2-3.5 micro by 0.2-1.0 micro in size. Most of the crystals found in the synovial fluid were rod-shaped. 4) X-ray microanalysis of the meniscus crystals by EMMA showed the same pattern of PK alpha, CaK alpha, and CaK beta content as that of CPPD crystals commercially available. The P/Ca ratio was about 0.7. 5) SEM and EMMA examination can be very useful for accurate identification of the form and content of the tiny crystals in joint tissues and synovial fluid. This can also be useful in proving a diagnosis of crystal-induced synovitis.

Calcinosis↗

Acceleration of experimental lapine osteoarthritis by calcium pyrophosphate microcrystalline synovitis.

OBJECTIVE: To investigate the effects of chronic calcium pyrophosphate dihydrate (CPPD) synovitis on the development of osteoarthritic (OA) lesions in an animal model. METHODS: OA was induced in the right knees of 30 male New Zealand white rabbits by partial lateral meniscectomy and section of the fibular collateral and sesamoid ligaments (PLM/LS), followed by 8 weekly intraarticular (IA) injections of 1 mg (low-dose) or 10 mg (high-dose) of CPPD crystals in 3 sets of experiments (10 rabbits each). The contralateral left knees served as controls: experiment 1 PLM/LS alone, experiment 2 8 weekly IA injections of CPPD crystals alone, and experiment 3 sham surgery plus 8 weekly IA injections of CPPD crystals. RESULTS: At 8 weeks, repeated IA injections of low-dose and high-dose CPPD crystals into meniscectomized right knees resulted in more severe OA than in meniscectomized but noninjected left knees (experiment 1) (P = 0.003 and P = 0.001, respectively). One-fourth of the meniscectomized knees (11 of 40), both CPPD-injected and noninjected, showed embedded synovial cartilage shards. CONCLUSION: The data demonstrate a worsening effect of chronic CPPD crystal-induced synovitis on experimental OA produced in the rabbit knees by PLM/LS, and support a possible role for CPPD microcrystalline inflammation in the progression of OA lesions in clinical CPPD crystal deposition disease.

Animals↗

Calcium pyrophosphate dihydrate crystal deposition disease mimicking malignant soft tissue tumor.

Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease has multiple clinical features with variable courses creating several pitfalls in clinical diagnosis. There are number of reported cases mimicking malignant skeletal tumors such as chondrosarcoma. However, no case of CPPD disease with radiographic noncalcified soft tissue mass has been reported in the literature. Here we report a case of CPPD disease clinically mimicking soft tissue tumor with its magnetic resonance imaging appearance and histopathology.

Aged↗

Hand and wrist involvement in calcium pyrophosphate dihydrate crystal deposition disease.

The clinical records and hand and wrist radiographs of 51 patients with calcium pyrophosphate dihydrate crystal deposition disease have been analyzed, and symptomatology and radiologic abnormalities have been correlated. Characteristic roentgenographic features included cartilage and synovial calcification and arthropathy of the metacarpophalangeal joints and the radiocarpal compartment of the wrist, including scapholunate dissociation. Clinical-radiologic correlation revealed many asymptomatic patients with calcification and arthropathy and many symptomatic patients with normal radiographs. Thorough radiologic evaluation may reveal many patients with this disorder before the onset of clinical symptoms.

Aged↗

A histologic and immunohistochemical study of calcium pyrophosphate dihydrate crystal deposition disease.

The articular cartilage, synovial membrane, and meniscus from ten patients who had calcium pyrophosphate dihydrate (CPPD) crystal deposition disease showed strong immunoreactivity for dermatan sulfate proteoglycan, Type I collagen, and S-100 protein in hypertrophic chondrocytes around the crystals, their pericellular matrix, and deposits of the crystals. Electron microscopy revealed that small crystals were formed around the hypertrophic chondrocytes, especially in the degenerated matrix containing electron-dense granular materials and cellular debris. Chondrocytes of this kind were never observed in the articular tissue from ten patients who had osteoarthrosis. These hypertrophic chondrocytes with several unique immunohistochemical characteristics may initiate the formation of CPPD crystals.

Aged↗

Scapholunate advanced collapse pattern of arthritis in calcium pyrophosphate deposition disease of the wrist.

Chondrocalcinosis is a well-described radiographic finding in patients with calcium pyrophosphate dihydrate deposition disease of the wrist and other joints. The medical records and x-ray films of 12 patients evaluated over an 18-month period for chondrocalcinosis of the wrist were examined for symptoms and physical and x-ray film findings. Thirteen wrists were affected. All wrists were noted to have calcification of the triangular fibrocartilage complex. Twelve of 13 wrists had the characteristic features of the scapholunate advanced collapse pattern of arthritis. In addition, there was a correlation in our series between chondrocalcinosis and carpal tunnel syndrome. Destruction of the interosseous soft tissues caused by crystalline deposition could alter the biomechanics of the wrist in a similar fashion to that of the post-traumatic scapholunate advanced collapse wrist leading to arthritic symptoms.

Aged↗

Regulation of alkaline phosphatase: implications for calcium pyrophosphate dihydrate crystal dissolution and other alkaline phosphatase functions.

OBJECTIVE: Alkaline phosphatase (ALP), an enzyme with pyrophosphatase (PPiase) activity can dissolve calcium pyrophosphate dihydrate (CPPD) crystals. We studied the effects of enzyme inhibitors such as bisphosphonates, orthovanadate, calcium, cadmium, and ascorbic acid on PPiase activity of ALP as well as on phosphate ester hydrolysis (Pase) activity and compared these effects to those on CPPD crystal dissolution. METHOD: An in vitro model system for crystal enzyme interaction was used to assess CPPD crystal dissolution. RESULTS: Bisphosphonates inhibited ALP Pase activity more than ALP PPiase activity at the same concentrations. Calcium inhibited ALP PPiase activity, but not ALP Pase activity. Orthovanadate and cadmium inhibited ALP PPiase activity more than ALP Pase at the same concentrations. The inhibition rates of ALP PPiase at the same concentrations were orthovanadate > cadmium > calcium. Although ALP Pase activity was not inhibited, at high concentrations, ascorbic acid slightly inhibited ALP PPiase activity. Bisphosphonates at high concentrations inhibited ALP CPPD crystal dissolution. The strong inhibitory effects of bisphosphonates on ALP CPPD crystal dissolution compared to those on ALP PPiase activity suggest that bisphosphonates inhibit crystal dissolution by their affinity for the CPPD crystal surface. Calcium, orthovanadate, and cadmium inhibited ALP CPPD dissolution. The inhibition rates of ALP CPPD dissolution at the same concentrations were cadmium > calcium > orthovanadate. Ascorbic acid at high concentrations enhanced ALP CPPD dissolution. CONCLUSION: These effects of different inhibitors on ALP PPiase and CPPD dissolution suggest that ALP CPPD crystal dissolution depends on binding of ALP CPPD crystals as well as the PPiase activity of the bound ALP. Because of its ubiquitous and broad phosphatase activity including PPiase activity, ALP may have a critical role in cell energy metabolism.

Alkaline Phosphatase↗

Tumoral calcium pyrophosphate dihydrate crystal deposition disease. A clinicopathologic analysis of five cases.

We describe five cases of tumoral calcium pyrophosphate dihydrate crystal deposition disease (CPPDCD) and discuss the clinical, radiological and pathological features. Patients included 4 males and 1 female, ranging in age from 49 to 70 years (median, 63 yrs). The wrist was involved in two patients. The thumb, palmar aspect of the proximal phalanx of the middle finger and dorsum of the carpal bone of the hand were involved in one patient each. In one patient, a preoperative diagnosis of chondrosarcoma had been made. Macroscopically, the lesion was a circumscribed whitish-gray mass with a more or less chalky appearance, measuring between 1.0 to 6.2 cm (median, 2.5 cm). Histologically, all five lesions contained areas of calcification with crystal deposits and chondroid metaplasia. The majority of crystals were rhomboid in shape, characteristic of CPPD, but some needle-shaped crystals were also identified, which resembled urate crystals. A review of the 54 reported cases of tumoral CPPDCD including our series indicated that they could be divided into two categories based on anatomic location: central (head and neck) type (n = 33) and distal (extremity) type (n = 21). Patients of these two groups were not different with respect to age and gender, but those with the central type often presented with a painful mass (15 patients, 46%), or neurological disturbances (11 patients, 33%). Patients with the distal type presented with a painless mass or swelling (12 patients, 57%), but none had neurological signs, although 8 (38.1%) presented with acute attack similar to tophaceous gout. Tumoral CP-PDCD should be differentiated from tophaceous gout, tumoral calcinosis, and malignant or benign tumors.

Aged↗

Cytosolic Ca2+ concentration determinations in neutrophils stimulated by monosodium urate and calcium pyrophosphate crystals: effect of protein adsorption.

OBJECTIVE: To develop methods to correct for light scattering artifacts produced by monosodium urate monohydrate (MSUM) and calcium pyrophosphate dihydrate (CPPD) crystals in the measurement of the levels of cytosolic free calcium, [Ca2+]i, in neutrophils and to quantitate the extent of association of neutrophils with crystals. METHODS: The association of neutrophils with crystals through binding of crystals onto the neutrophil plasma membrane and/or internalization was quantitated by mixing crystals with diphenyl hexatriene (DPH) loaded neutrophils and monitoring the fluorescence intensity of supernatants ("free" neutrophils) following gravity sedimentation of "free" crystals and neutrophils with bound/internalized crystals. The effects of precoating CPPD and MSUM crystals with IgG, plasma, serum and BSA on crystal-neutrophil association and [Ca2+]i were determined. RESULTS: MSUM produced a large increase in [Ca2+]i that reached maximal values in less than 1 min, whereas CPPD produced a smaller and slower increase in [Ca2+]i. IgG adsorbed onto CPPD increased the rate and extent of increase in [Ca2+]i. Heparinized plasma and serum adsorbed onto CPPD increased the extent but not the rate of increase in [Ca2+]i. CONCLUSION: [Ca2+]i increases induced by MSUM were not affected by IgG, serum or heparinized plasma precoating. IgG, serum, or heparinized plasma adsorbed into CPPD amplified neutrophil activation increasing the extent of the increase in [Ca2+]. Neither MSUM nor CPPD induced increases in [Ca2+]i were sensitive to precoating crystals with bovine serum albumin.

Adsorption↗

Enhancement of crystal induced neutrophil responses by opsonisation of calcium pyrophosphate dihydrate crystals.

OBJECTIVES: Little is known about the effect on crystal induced neutrophil responses of the opsonisation of calcium pyrophosphate dihydrate (CPPD) (triclinic) crystals with components of serum and plasma. The purpose of this study was to determine the effects of precoating CPPD crystals with plasma, serum, complement depleted serum, and IgG on a full range of crystal induced neutrophil responses (calcium mobilisation, chemiluminescence, superoxide anion production, non-cytolytic lysosomal enzyme release, and leukotriene synthesis). METHODS: Crystals were precoated with IgG, serum, plasma, or complement depleted serum (heated at 56 degrees C), incubated with neutrophils and the responses monitored with time. Measurement of the extent of neutrophil association with crystals was based on monitoring the decrease in fluorescence intensity of supernatants when crystals and diphenylhexatriene labelled neutrophils were allowed to settle under gravity. RESULTS: Precoating CPPD crystals with IgG, plasma, and serum significantly enhanced chemiluminescence, superoxide anion generation, increases in cytosolic free calcium levels, and non-cytolytic lysosomal enzyme release by neutrophils compared with uncoated CPPD crystals. The enhancement of neutrophil responses by crystals coated with complement depleted serum was less pronounced. The increased neutrophil responses induced by CPPD crystals coated with IgG might have been due to the observed increase in the association of IgG coated crystals with neutrophils. CONCLUSIONS: These data show that there is a marked potentiation of all neutrophil responses to IgG, plasma, and serum coated CPPD crystals. It is suggested that the adsorption of synovial fluid proteins, including IgG and C3b, to CPPD crystals in vivo, results in the opsonised crystals becoming a potent neutrophil stimulant and inflammatory agent.

Animals↗

Polyamines enhance calcium pyrophosphate dihydrate crystal dissolution.

OBJECTIVE: Alkaline phosphatase (ALP), an enzyme with pyrophosphatase (PP(i)ase) activity, can dissolve calcium pyrophosphate dihydrate (CPPD) crystals. We investigated the CPPD crystal dissolution activity of polyamines, substrates known to enhance PP(i)ase activity. METHODS: An in vitro model system for crystal enzyme interaction was used to assess CPPD crystal dissolution both biochemically and morphologically. RESULTS: We demonstrated biochemically and morphologically that polyamines such as spermine and spermidine can enhance CPPD crystal dissolution activity of ALP. Polyamines enhanced ALP induced CPPD crystal dissolution and ALP PP(i)ase activity differentially. By scanning electron microscopy, we observed that polyamines enhanced dissolution stereoselectively at the small end faces (optical 010 faces) of CPPD crystals, indicated by the presence of etch pits. CONCLUSION: Polyamines assist ALP to promote the stereoselective dissolution of CPPD crystals. In addition to implications for CPPD crystal dissolution, as ALP is present intracellularly, these studies suggest that polyamines and ALP have synergistic effects when ALP PP(i)ase activity is required for intracellular energy metabolism.

Alkaline Phosphatase↗

Effect of joint motion on experimental calcium pyrophosphate dihydrate crystal induced arthritis.

We studied the effects of joint movement and immobilization on acute and chronic calcium pyrophosphate dihydrate (CPPD) crystal induced arthritis in lapine knee joints. Exercised CPPD injected joints, in both acute (single 10 mg CPPD intraarticular (IA), duration: 5 h) and chronic (repeated 10 mg CPPD IA, duration: 20 and 42 days) experiments, demonstrated a more intense histologic synovitis compared to cast immobilized knees (p = 0.0001). In chronic experiments, both CPPD injected and noninjected immobilized knees showed greater cartilage histopathologic-histochemical abnormalities (p less than 0.004) and significant reduction in cartilage hexosamine content (p less than 0.005), compared to exercised joints. CPPD injected knees, both exercised and immobilized, demonstrated an initial phase of increased cartilage biosynthetic activity (35S incorporation) at 20 days, compared to noninjected knees (p = 0.02), followed by a decline at 42 days (p less than 0.005). Our data indicate that joint movement enhances acute and chronic experimental CPPD crystal induced synovitis. Articular cartilage is more adversely affected by joint immobilization than by chronic crystalline inflammation. An optimum balance between exercise and rest seems necessary for patients with arthritis so that cartilage can be preserved but pain from active inflammation also controlled.

Animals↗

Diagnosis of calcium pyrophosphate dihydrate crystal deposition disease: ultrasonographic criteria proposed.

OBJECTIVE: To investigate by high frequency ultrasonography the appearance of calcium pyrophosphate dihydrate (CPPD) calcifications, in the most commonly affected sites in CPPD disease, and the relationship between ultrasonographic CPPD deposits and the presence of CPPD crystals in synovial fluid. METHODS: Three ultrasonographic patterns of CPPD calcification were identified and 11 patients enrolled. A control group comprised 13 patients with no evidence of CPPD deposits. Synovial fluid was aspirated from all patients and controls and examined for identification of crystals. All patients underwent a standard radiography examination at the same sites investigated by ultrasound. RESULTS: In all patients with ultrasonographically defined CPPD deposits, CPPD crystals were found in the synovial fluid. In two cases, standard radiographic examination did not show evidence of the calcific deposits that were identified by ultrasonography. CPPD crystals were not found in the synovial fluid of controls. In four control group patients, ultrasonography identified calcifications defined as deposits of another nature. CONCLUSIONS: The ultrasonographic pattern used in this study for the diagnosis of CPPD disease demonstrated a very high correlation with the presence of CPPD crystals in synovial fluid. Ultrasonography demonstrated a sensitivity and specificity at least equal to that of radiography in identifying CPPD crystal calcifications.

Aged↗

The utility of alizarin red s staining in calcium pyrophosphate dihydrate crystal deposition disease.

OBJECTIVE: To determine the most suitable staining method for preservation and detection of calcium pyrophosphate dihydrate (CPPD) crystals in histological sections of patients with CPPD crystal deposition disease. METHODS: Paraffin sections of CPPD crystal-bearing tissues of 31 patients were stained with hematoxylin and eosin (H&E) and Alizarin red S (ARS). For H&E, the sections were treated with Mayer's hematoxylin (pH 2.3) for 5 min and with eosin alcohol (pH 4.1) for 1 min. For ARS, 1% ARS dissolved in distilled water was adjusted to pH 6.4 by adding 0.1% ammonia solution drop by drop while stirring. As controls, unstained sections were soaked in 1% citric acid monohydrate solution (CAMS, pH 2.3) for 5 or 10 min. The histological preparations were examined under a compensated polarized light using a first-order red compensator. We counted the number of weakly positive birefringent CPPD crystals in 3 high power fields (HPF, 0.272 mm2). RESULTS: CPPD crystals were seen clearly in most specimens stained with ARS, but were markedly reduced in tissue sections stained with H&E or CAMS. The number of CPPD crystals detected in sections stained by ARS (1723 +/- 683 per 3 HPF, mean +/- standard deviation) was significantly higher compared with H&E, CAMS (5 min), and CAMS (10 min) (401 +/- 374, 1022 +/- 616, and 494 +/- 636 per 3 HPF, respectively; p < 0.001, each). CONCLUSION: Standard H&E staining reduces the number of visible CPPD crystals, probably due to the strong acidity of both hematoxylin and eosin solutions, whereas the ARS stain seems to preserve a large number of CPPD crystals. The utility of ARS staining may improve the identification of CPPD crystals and contribute to a correct diagnosis of CPPD crystal deposition.

Aged↗

Tumourous deposition of calcium pyrophosphate dihydrate crystals in the wrist. A case report.

A 63-year-old man had a tumourous deposition of calcium pyrophosphate dihydrate crystals in the palmar aspect of the wrist. Traumatic micro-fracture or osteoarthritis was thought to have triggered the deposition of these crystals. It should be possible to differentiate the lesion clinically and radiologically from tumoural calcinosis, in which the deposits consist of calcium carbonate and/or calcium phosphate.

Calcium Pyrophosphate↗

Effect of synthetic calcium pyrophosphate and hydroxyapatite crystals on the interaction of human blood mononuclear cells with chondrocytes, synovial cells, and fibroblasts.

Synthetic calcium pyrophosphate dihydrate crystals and, to a lesser extent, synthetic hydroxyapatite crystals increased the amount of interleukin-1/mononuclear cell factor released by human blood monocytes, as measured by collagenase and prostaglandin E2 production by rabbit chondrocytes, human dermal fibroblasts, and adherent rheumatoid synovial cells. The same crystals also directly induced collagenase and prostaglandin E2 secretion by rabbit chondrocytes, and potentiated the action of interleukin-1/mononuclear cell factor on chondrocytes. These mechanisms may be important in the pathogenesis of the destructive arthropathies associated with these crystals.

Animals↗