Pressure erosions: rheumatoid arthritis or calcium pyrophosphate dihydrate crystal deposition disease?
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Arthritis, Rheumatoid↗
Biomedical subjects
D J McCarty
Publications and source records attributed to D J McCarty.
Mitogenic activity of hydroxyapatite: requirement for somatomedin C.
Synovial hyperplasia is a feature of the chronic synovitis associated with basic calcium phosphate crystals [hydroxyapatite (HA), octacalcium phosphate, tricalcium phosphate] and calcium pyrophosphate. Each of these crystals stimulated mitosis of cultured human skin fibroblasts or canine synovial fibroblasts in a concentration-dependent fashion. We examined the effect of pure somatomedin C (Sm-C) on HA crystal induced mitogenesis. Confluent cultures of human fibroblasts were rendered quiescent by incubation in the presence of 1% platelet-poor-Sm-C free plasma (PPSCFP) for 24 hours. HA crystals stimulated thymidine incorporation 2.3-fold over control value. Addition of Sm-C significantly augmented the effect of HA crystals (P less than 0.01). Nearly identical effects were observed in the presence of 100 micrograms/ml HA crystals or 15 ng/ml PDGF. Monoclonal antibodies against Sm-C had little effect on the basal 3H thymidine uptake by control cells incubated in 1% PPSCFP but blocked over 50% of the HA crystal or PDGF-induced 3H thymidine incorporation both in the presence or absence of Sm-C. The incomplete blocking suggested either the presence of other "progression" factors, such as insulin-like growth factor II in the conditioned media or the possibility that HA or PDGF in high enough dosage enabled cells to escape their dependence on Sm-C for DNA synthesis.
Cells, Cultured↗
Endocytosis precedes dissolution of basic calcium phosphate crystals by murine macrophages.
Murine peritoneal macrophages were incubated with 45Ca-labeled basic calcium phosphate (BCP) crystals in the presence or absence of cytochalasin B. Untreated macrophages solubilized 30-50% of 45Ca-BCP in 24 hours. Dissolution began within 3 hours and was linear thereafter. Twenty-three percent of BCP was cell-associated by 3 hours. Endocytosis of crystal occurred continuously throughout the incubation. Endocytosis of crystal did not affect the migration of macrophages through Percoll density gradients. Addition of cytochalasin B did not prevent cell-association of BCP, but inhibited solubilization in a dose-dependent manner. Virtually all cell-associated BCP was removed when cytochalasin B-treated cells were washed with EDTA, suggesting that the crystals were only bound to the surface. In contrast, cell-associated BCP in untreated cells was only partially removed by EDTA, suggesting that endocytosis of crystal had occurred. We conclude that cell association of BCP is not sufficient for its dissolution, and that endocytosis precedes solubilization of BCP crystals by macrophages.
Animals↗
Arthritis associated with crystals containing calcium.
Varying combinations of acute inflammatory and/or chronic degenerative arthritis have been found to be associated with crystals of calcium pyrophosphate dihydrate (CPPD) and/or basic calcium phosphates (BCPs). Since the arthropathies associated with CPPDs and/or BCPs occur in older individuals, while diagnosis and treatment for monosodium urate monohydrate crystal deposition disease (gout) have become extremely precise and effective, joint problems associated with calcium crystals have become more common than those associated with monosodium urate monohydrate crystals. The classification, pathogenesis, clinical manifestations, and treatment of CPPD and BCP crystal deposition are discussed.
Aged↗
Patterns of radiographic abnormalities associated with basic calcium phosphate and calcium pyrophosphate dihydrate crystal deposition in the knee.
Radiographs and synovial fluids from 66 knees representing 59 patients with symptomatic osteoarthritis were evaluated to determine the pattern of radiographic abnormalities associated with basic calcium phosphate (BCP), calcium pyrophosphate dihydrate (CPPD), or both crystals together. Crystals were found in 71% of fluids. In general, CPPD crystals correlated with patient age, while BCP crystals correlated with joint degeneration. Synovial fluid BCP and CPPD crystals were found together more often than either alone. Joint compartment narrowing and osteophytes in three compartments are often associated with BCP crystals.
Aged↗
Pyrophosphohydrolase activity and inorganic pyrophosphate content of cultured human skin fibroblasts. Elevated levels in some patients with calcium pyrophosphate dihydrate deposition disease.
In calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, metabolic abnormalities favoring extracellular inorganic pyrophosphate (PPi) accumulation have been suspected. Elevations of intracellular PPi in cultured skin fibroblasts from a single French kindred with familial CPPD deposition (19) and elevated nucleoside triphosphate pyrophosphohydrolase activity (NTPPPH), which generates PPi in extracts of CPPD crystal-containing cartilages (14) favor this suspicion. To determine whether NTPPPH activity or PPi content of cells might be a disease marker expressed in extraarticular cells, human skin-derived fibroblasts were obtained from control donors and patients affected with the sporadic and familial varieties of CPPD (CPPD-S and CPPD-F) deposition. Intracellular PPi was elevated in both CPPD-S (P less than 0.05) and CPPD-F (P less than 0.01) fibroblasts compared with control fibroblasts. Ecto-NTPPPH activity was elevated in CPPD-S (P less than 0.01) but not CPPD-F. Intracellular PPi correlated with ecto-NTPPPH (P less than 0.01). Elevated PPi levels in skin fibroblasts may serve as a biochemical marker for patients with familial or sporadic CPPD crystal deposition disease; ecto-NTPPPH activity further separates the sporadic and familial disease types. Expression of these biochemical abnormalities in nonarticular cells implies a generalized metabolic abnormality.
Calcium Pyrophosphate↗
Remitting seronegative symmetrical synovitis with pitting edema. RS3PE syndrome.
Eight elderly men and two elderly women presented with symmetrical polysynovitis of acute onset involving most of their appendicular joints and flexor digitorum tendons associated with pitting edema of the dorsum of both hands and both feet. Onset of seven of the ten cases could be pinpointed almost to the hour. Rheumatoid factors were absent from serum samples in all, and no radiologically evident erosions developed. Clinical and laboratory signs of inflammation and the edema disappeared gradually in each case. Treatment consisted of aspirin or other nonsteroidal anti-inflammatory drugs. Hydroxychloroquine, 200 to 400 mg/day, was given in six and gold therapy in two cases. Painless limitation of motion of the wrists and/or fingers persisted in all, although the patients were both unaware of and unhampered by this abnormality. Six of eight cases where typing was possible were positive for HLA-B7, CW7, and DQW2 (relative risk for B7, 9.5). Three cases of this syndrome were found in a consecutive series of 52 men diagnosed as having definite "rheumatoid arthritis," and thus represent a distinctive condition with an excellent prognosis.
Acute Disease↗
Cartilage nucleoside triphosphate pyrophosphohydrolase. II. Role in extracellular pyrophosphate generation and nucleotide metabolism.
Extracellular generation of inorganic pyrophosphate (PPi) in cartilage organ culture is markedly augmented by ATP.ATP, not an ATP metabolite (ADP, AMP, adenosine) is necessary for this augmentation. Excess PPi production is effectively blocked by known inhibitors of nucleoside triphosphate (NTP) pyrophosphohydrolase (EDTA, EGTA, dithiothreitol). Excess 32P-PPi is generated directly from gamma 32P-ATP by cartilage, as substrate and product have similar specific activities. These findings strongly favor ecto-NTP pyrophosphohydrolase as the source of extracellular PPi generation in the presence of NTP. Additionally, active nucleotide and nucleoside catabolism is demonstrated in these cartilage organ cultures.
Adenosine Triphosphate↗
Calcium pyrophosphate dihydrate crystal deposition in rheumatoid arthritis.
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Aged↗
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↗
Simple method for measurement of lower extremity muscle strength.
A simple, rapid, reproducible method for quantification of lower extremity muscle strength was standardized. The time needed to stand 10 times from a standard chair was recorded in 139 healthy subjects, aged 20 to 85 years (77 men, 62 women). Reproducibility was 6.8 percent (+/- 3.4 percent). Neither height nor weight was related to time in either sex. Weight was related to time (p less than 0.05) after adjusting for age, but this effect was slight compared with the effect of age alone. A highly significant (p less than 0.0001) relationship between time and age was found in both sexes. Younger men performed better than younger women, although this difference was lost in the older age groups. The results of this simple test correlated well with published data on the strength of knee flexor and extensor muscles in groups of men and women of various ages. This method was used to evaluate serially six consecutive patients with classic polymyositis or dermatomyositis. Improvement after treatment with prednisone used alone or in combination with azathioprine or methotrexate was found in all cases.
Adult↗
Mitogenesis induced by calcium-containing crystals. Role of intracellular dissolution.
Hydroxyapatite, like other calcium-containing crystals previously studied by us, is mitogenic for cultured human fibroblasts. This mitogenic effect is not a result of increased ambient calcium concentration due to extracellular crystal dissolution. Synthetic crystals labelled uniformly with calcium 45 (45Ca) undergo endocytosis when incubated with cells and are solubilized. Such solubilization is inhibited by chloroquine or ammonium chloride in concentrations that significantly block the mitogenic effect of crystals but not that of serum. The data suggest that mitogenesis and intracellular crystal dissolution are related phenomena.
Ammonium Chloride↗
Prostaglandin (PG) E2 generation by cultured canine synovial fibroblasts exposed to microcrystals containing calcium.
Immunoreactive prostaglandin (PG) E2 was released into the ambient medium in a dose dependent fashion when either hydroxyapatite (HA) or calcium pyrophosphate dihydrate (CPPD) crystals were added to canine synovial fibroblasts in tissue culture. PGE2 release peaked 6 to 9 hours after HA or CPPD crystals were added in the presence of serum but at 24 hours if they were added in the presence of lactalbumin hydrolysate. PGE2 release correlated with crystal endocytosis estimated qualitatively by serial phase contrast microscopy and time lapse photography. As postulated previously by others for monosodium urate crystals, prostaglandin production by synovial cells may also be related to the pathogenesis of the destructive arthropathies associated with HA or CPPD crystals.
Animals↗
Gold induced aplastic anemia. Complete response to corticosteroids, plasmapheresis, and N-acetylcysteine infusion.
A 47-year-old woman with rheumatoid arthritis (RA) had been treated with greater than 7 g of gold sodium thiomalate over a 5 year period when aplastic anemia developed. Treatment with corticosteroids, plasmapheresis and infusion of N-acetylcysteine (NAC) resulted in complete hematologic remission. Infusion of NAC increased daily urinary excretion of gold and use of an ambulatory infusion pump with a Hickman catheter allowed protracted outpatient infusion for more than 4 months' duration. It is now 20 months since the onset of aplastic anemia and she remains in complete hematologic remission.
Acetylcysteine↗
Cartilage nucleoside triphosphate (NTP) pyrophosphohydrolase. I. Identification as an ecto-enzyme.
When 1 mM ATP was added to ambient media of canine cartilage in organ culture or canine chondrocytes in monolayer culture, PPi was generated linearly over 4 hours. The appearance of PPi was related to an ectoenzyme based upon its ability to act upon extracellular substrate, to generate extracellular products, failure to detect enzyme activity in supernatant media, failure to increase activity by cell disruption, and susceptibility to digestion by extracellular trypsin. The enzyme responsible for PPi generation is nucleoside triphosphate (NTP) pyrophosphohydrolase, which acts upon a number of purine and pyrimidine nucleoside triphosphates. This enzyme may play a role in generation of extracellular PPi which participates in calcium pyrophosphate dihydrate crystal formation.
Adenosine Triphosphate↗
Clearance of 85Sr-labeled calcium phosphate crystals from rabbit joints.
The clearance of basic calcium phosphate crystals from rabbit joints was studied using synthetic crystals with characteristics similar to natural joint fluid mineral phase. Addition of strontium 85 during synthesis resulted in uniform trace-labeling. Crystals were rapidly taken up by synovial lining cells after intrasynovial injection. The time for clearance of one-half of the injected basic calcium phosphate crystal mass was 6.7 days, approximately 3 times faster than found previously for the much larger calcium pyrophosphate dihydrate crystals.
Animals↗
Mitogenic effects of hydroxyapatite and calcium pyrophosphate dihydrate crystals on cultured mammalian cells.
Synthetic hydroxyapatite (HA) crystals in 1% serum stimulated 3H thymidine uptake into quiescent canine synovial fibroblasts and human foreskin fibroblast cultures, as did 10% serum. The onset of stimulation and peak uptake of thymidine after crystal addition were delayed by 2-3 hours as compared with the effects produced by 10% serum. Stimulation of 3H thymidine uptake was proportional to the serum concentration used. HA crystals (50 micrograms/ml) stimulated nuclide uptake at each serum concentration used. 3H thymidine uptake was also proportional to the dose of HA or calcium pyrophosphate dihydrate crystals, although larger doses of the latter crystal were required to produce equivalent effects. Not all particulates were effective mitogenic agents. Latex beads and diamond crystals had no effect. Monosodium urate crystals modestly stimulated and calcium urate crystals markedly stimulated nuclide uptake. The more complex crystals found in a naturally occurring condition (calcinosis) were as mitogenic as the pure synthetic HA. The synovial cell hyperplasia sometimes associated with crystals might be explained in part by their mitogenic activity.
Animals↗
Cultured canine synovial cells solubilize 45Ca-labeled hydroxyapatite crystals.
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Animals↗