Calcium crystal-induced inflammation.

Recent studies have added to our knowledge regarding the mechanisms of calcium crystal deposition. Calcium pyrophosphate dihydrate (CPPD) crystal deposition is associated with elevated levels of PPi in joints. Cyclic compression of cartilage transiently elevated ATP levels in culture media. Extracellular ATP may be hydrolyzed by nucleoside triphosphate pyrophosphohydrolase (NTPPPH), yielding an elevated PPi concentration. CPPD crystal deposition increases with age. Nitric oxide may alter cartilage matrix by interfering with chondrocyte mitochondrial function and ATP production. Transglutaminase in adult, but not young, porcine articular chondrocytes was able to activate latent transforming growth factor beta, a potent stimulus to PPi production. Basic calcium phosphate crystals are more likely to form in a milieu of reduced PPi concentration. The ank gene mutation results in higher intracellular PPi concentration and lower extracellular concentration. The ANK protein is thought to be a transmembrane protein necessary for transport of PPi out of cells. A mutation that results in reduced synthesis of NTPPPH PC-1 caused infantile wrist and ankle periarticular calcification and vascular calcification.

Nonsteroidal antiinflammatory drugs: benefits, risks, and COX-2 selectivity.

Nonsteroidal antiinflammatory drugs (NSAIDs) are the most frequently prescribed class of medication for arthritis and other musculoskeletal disorders. NSAIDs block prostaglandin production, thereby reducing pain and inflammation, but may also cause significant side effects, particularly ulcers in stomach and duodenum. Some risk factors include age, previous history of ulcer, and high dose of NSAID. Synthetic prostaglandins, H2 blockers, and proton pump inhibitors have been employed to reduce risks with varying degrees of success. New NSAIDs that block only prostaglandins at sites of inflammation (COX-2 selective NSAIDs) may be significantly safer than traditional NSAIDs.

Intracellular calcium responses to basic calcium phosphate crystals in fibroblasts.

OBJECTIVE: To examine the intracellular calcium response to basic calcium phosphate (BCP) crystals in fibroblasts. DESIGN: In this study, intracellular calcium [Ca2+]i levels in fibroblasts were determined using the photoactive dye, fura-2. Interruption of these responses was accomplished by either removal of Ca2+ from the extracellular medium or addition of ammonium chloride that inhibits intracellular dissolution of BCP crystals by alkalinizing phagolysosomes. The effects of such interruptions on BCP induction expression of proto-oncogenes were demonstrated by the Northern blot analysis. RESULTS: Addition of media containing BCP crystals yielded an immediate 10-fold rise of [Ca2+]i over the baseline level in human fibroblasts. This peak was derived mostly from extracellular calcium and was not seen when BCP crystals in calcium-free media were added to fibroblasts. The [Ca2+]i concentration returned to the baseline level within 8 min. A second rise of [Ca2+]i started at 60 min and continued to increase up to at least 3 h. This peak was derived from intracellular dissolution of phagocytosed crystals and almost completely inhibited by 10 mM ammonium chloride. CONCLUSION: The initial transient [Ca2+]i increase probably serves as a second messenger leading to activation of early cellular responses such as c-fos expression which is important in BCP crystal-induced mitogenesis. The second, slower and more sustained rise of [Ca2+]i probably initiates other cellular processes needed for fibroblast mitogenesis.

The spondyloarthropathies.

The spondyloarthropathies represent a heterogeneous group of arthropathies including ankylosing spondylitis, reactive arthritis with Reiter syndrome as one subtype, arthritis associated with inflammatory bowel disease, arthritis associated with psoriasis, and juvenile spondyloarthritis. These conditions are linked by several common features: inflammatory arthritis involving the back, a high prevalence of HLA-B27, frequent tendon/ligament insertion inflammation, and several common extra-articular manifestations (iritis, skin lesions). Although not uncommon, these types of arthritis are more difficult to recognize than other types of arthritis such as osteoarthritis and rheumatoid arthritis.

Calcium crystal-associated diseases.

The significance of calcium-containing crystals is unknown. Circumstantial evidence suggests that crystals are associated with more severe arthritis. Addition of calcium pyrophosphate dihydrate crystals to a lapine meniscectomy model of osteoarthritis resulted in greater damage to cartilage compared with meniscectomy alone. Elimination of calcium pyrophosphate dihydrate crystals may occur extracellularly by enzymatic degradation. Spermine and spermidine both enhance the degradative activity of alkaline phosphatase on crystals. In familial calcium pyrophosphate dihydrate crystal deposition disease, genetic heterogeneity is likely because one family demonstrated a linkage to chromosome 8q, whereas another did not. Tumoral deposition of calcium pyrophosphate dihydrate crystals may occur in single locations without radiographic chondrocalcinosis in other joints. Hydroxyapatite crystals are found in the ligamenta flava from surgical specimens but not as tumoral depositions. Magnesium whitlockite crystals have been found not only in osteoarthritic articular cartilage but also in normal cartilage, suggesting that these crystals may be nonpathologic in at least some cases.

Extraarticular manifestations of rheumatoid arthritis.

Rheumatoid arthritis affects joints and other systems in the body. Dryness of the eyes and mucous membranes are referred to as Sjogren's Syndrome. The heart is usually spared but the lungs can be affected by pleurisy, scarring, and the formation of nodules in the lungs. The nervous system may be involved by compression neuropathy (e.g. carpal tunnel syndrome), peripheral neuropathy, or occasionally from cervical cord compression. The rare complication of vasculitis (inflammation of blood vessels) may be devastating because of gangrene or severe internal organ damage. Some of the effects of rheumatoid arthritis may be "invisible" such as anemia or abnormalities in the white blood cell count. Osteoporosis is usually asymptomatic until a fracture occurs.

Phosphocitrate prevents disease progression in murine progressive ankylosis.

OBJECTIVE: Mice with progressive ankylosis, a spontaneous arthropathy, were treated with phosphocitrate (PC) in vivo to determine the effect of PC on disease progression. METHODS: Two groups of mice with progressive ankylosis (matched for age, weight, and sex) were treated parenterally for 6 weeks with either PC or saline vehicle. RESULTS: Clinically, histologically, and microradiographically, there were significant differences in disease progression and severity in the PC-treated and the saline-treated mice. CONCLUSION: PC appears to inhibit disease progression in murine progressive ankylosis.

Systemic lupus erythematosus: medical and nursing treatments.

Systemic lupus erythematosus is a multisystem autoimmune disease that may affect skin, joints, mucous membranes, heart, lungs, kidneys, nervous system and all the blood cell lines. Although its cause is unknown, abnormal immune function results in the formation of antibodies directed against various components of the human body (autoantibodies). Treatment depends of the severity of the illness and may include nonsteroidal antiinflammatory agents for arthritis; antimalarial therapy for skin disease and other mild lupus manifestations; and corticosteroids and immunosuppressive agents including azathioprine, cyclophosphamide, and methotrexate for more severe lupus manifestations. Persons affected by lupus and their families need help in understanding the condition and require support as they deal with fear, depression, and possible disability. Implications for nursing are varied and include patient/family education about medication, joint protection principles, energy conservation, pain and stress management, and coping techniques.

Arthropathies associated with basic calcium phosphate crystals.

Basic calcium phosphate (BCP) crystals refer to a family of crystals including partially carbonate substituted hydroxyapatite, octacalcium phosphate, and tricalcium phosphate. These crystals have been found in and around joints and have been associated with several forms of arthritis and periarthritis. Identification of BCP crystals remains problematic because of the lack of a simple, reliable analytic procedure. Methods currently in use include alizarin red S staining, labelled diphosphonate binding, scanning and transmission electron microscopy with energy dispersive X-ray microanalysis, X-ray diffraction, and atomic force microscopy. Periarthropathies associated with BCP crystals include calcific tendinitis and bursitis. Intra-articular BCP crystal deposition is common in osteoarthritis, often found together with calcium pyrophosphate dihydrate crystals. Uncommon conditions in which BCP crystals are found include destructive shoulder arthropathies, acute inflammatory attacks of arthritis, and erosive arthritis. Secondary deposition of BCP crystals has been observed in chronic renal failure, in patients with "collagen vascular" diseases, following neurologic injury and after local corticosteroid injection.

Simultaneous occurrence of calcium pyrophosphate dihydrate and basic calcium phosphate (hydroxyapatite) crystals in a knee.

An 82-year-old man developed periarticular roentgenographic calcifications of the knee joint. Fragments of meniscus and peritendinous tissue were collected during total knee arthroplasty. Crystals were released from tissues by collagenase digestion. Calcium pyrophosphate dihydrate crystals were identified in the meniscus, and basic calcium phosphate crystals were identified in the peritendinous tissue. Methods of crystal identification included compensated polarized light microscopy, scanning electron microscopy with X-ray energy dispersive analysis, and X-ray diffraction.

Milwaukee shoulder syndrome. Fifteen additional cases and a description of contributing factors.

Fifteen additional patients with Milwaukee shoulder syndrome are described, bringing our total series to 30 cases. The condition occurred predominantly in elderly women and was characterized by severe glenohumeral joint degeneration and dissolution of the fibrous rotator cuff. Synovial fluids contained few leukocytes, but were often blood tinged. Basic calcium phosphate crystal aggregates and particulate collagens were noted in nearly all fluids, and collagenase activity was detectable in some, but not all, fluids. The knee joints were involved with a similar process in about half of our patients. In contrast to primary osteoarthritis, lateral tibiofemoral compartment involvement was common. Factors that may predispose to this syndrome included deposition of calcium pyrophosphate dihydrate crystals, direct trauma or chronic joint overuse, chronic renal failure, and denervation.

Calcium pyrophosphate crystal deposition: a kinetic study using a type I collagen gel model.

Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is characterized by deposits of triclinic (t) and monoclinic (m) CPPD crystals in articular and fibrocartilage. Many investigators have attempted to model CPPD crystal growth using both solution and a variety of gel systems. We have investigated the effect of type I collagen fibrils on CPPD crystal nucleation and growth using an ionic diffusion model. Collagen was isolated from porcine menisci using a pepsin solubilization procedure and gelled in three layers, with one containing 10 mM pyrophosphate (PPi) plus physiologic ions, the middle containing only the ions, while the third contained 25 mM Ca plus physiologic ions. Initially, amorphorous calcium pyrophosphate formed at the Ca-PPi interface. Monoclinic CPPD crystallized in 6 weeks when the [Ca] was between 2 and 3 mM and the [PPi] was between 50 and 75 microM. At 13 weeks, t-CPPD formed when the [Ca] was also between 2 and 3 mM, but the PPi was less than 25 microM. One of the most striking differences between this system and all previous solution and gel model systems is the total absence of orthorhombic calcium pyrophosphate tetrahydrate (o-CPPT) from the gels made of collagen fibrils in near native conformation. Further, crystals of t-CPPD appear as large single crystals with the classic prismatic growth habit observed in vivo, and crystals of m-CPPD also evidence the in vivo rod habit. In contrast, the crystal growth habits of t-CPPD, m-CPPD, and o-CPPT grown in all of the other model systems never matched that observed in vivo. When compared to the previous studies, these results, particularly the crystal growth habit data, suggest that the native collagen fibrils themselves can nucleate CPPD crystal formation.

Triple crystal disease: monosodium urate monohydrate, calcium pyrophosphate dihydrate, and basic calcium phosphate in a single joint.

A 49 year old man is described with a polyarticular arthritis. Synovial fluid aspirated from the knee joint showed monosodium urate monohydrate and calcium pyrophosphate dihydrate by polarised light microscopy. Additionally, diphosphonate binding and scanning electron microscopy with energy dispersive analysis showed that basic calcium phosphate crystals were also present. This appears to be the first report of three crystals occurring simultaneously in a single joint.

Clinical aspects of basic calcium phosphate crystal deposition.

Our present understanding of the mechanisms of pathologic calcification is quite limited. Therefore, no reliable method exists to prevent calcium crystal deposition. Low doses of warfarin have been employed in some cases of soft tissue calcification because it depresses the synthesis of the vitamin K-dependent GLA protein (gamma carboxyglutamic acid), which has been implicated in the process of calcification. Reports of success must be tempered by the lack of a controlled study. Probenecid has also been utilized in the treatment of calcinosis.

Calcium pyrophosphate crystal deposition: the effect of soluble iron in a kinetic study using a gelatin matrix model.

The kinetics of calcium pyrophosphate dihydrate (CPPD) crystal growth was studied by allowing calcium and pyrophosphate (PPi-4) ions to diffuse through a denatured collagen matrix (biological grade gelatin) in the presence of either ferric or ferrous ions. Ferric and, to some extent, ferrous ions blocked the migration of the PPi-4 diffusion gradient. This retardation in the [PPi-4] gradient led to numerous changes in the patterns of CPPD crystal formation. At the initial stages of crystal growth, the iron ions induced more crystal growth compared to control. At later incubation times, ferrous and ferric ions enhanced crystal growth at the expense of crystal nucleation. The presence of both ferrous and ferric ions resulted in the more rapid formation of the two crystals observed in vivo, triclinic CPPD and monoclinic CPPD. Further, both ferrous and ferric ions also reduced the solubility of the crystalline material in the broad diffuse band which formed when the Ca+2 and PPi-4 gradients first met. In this system, the presence of either ferrous or ferric ions increased the amount of hydroxyproline included in the crystalline precipitates. Iron was also incorporated into the crystals, particularly into the triclinic CPPD and monoclinic CPPD crystals.

Calcium pyrophosphate crystal deposition: the effect of monosodium urate and apatite crystals in a kinetic study using a gelatin matrix model.

The kinetics of calcium pyrophosphate dihydrate (CPPD) crystal growth was studied by allowing calcium and pyrophosphate (PPi-4) ions to diffuse through a denatured collagen matrix (biological grade gelatin) in the presence of either monosodium urate monohydrate (MSU) or hydroxyapatite (HA) crystals. In this in vitro model system, MSU crystals significantly altered the kinetics of PPi-4 ionic diffusion through the gelatin matrix by allowing the [PPi-4] gradient to fall off much more rapidly, suggesting an increased level of scavenging of PPi-4 ions into crystalline materials. Even more significantly, the presence of MSU crystals markedly influenced the crystal growth morphology of triclinic CPPD, producing that observed in vivo. A large number of epitaxially dimensional matches between MSU and triclinic (t) and monoclinic (m) CPPD were identified, suggesting that MSU crystals can epitaxially induce CPPD crystal growth. This finding supports the hypothesis that the association of urate gout and CPPD crystal deposition disease is based on the nucleating potential of MSU crystals for CPPD crystal growth. In contrast, the HA crystal structure did not appear to serve as a nucleating agent for CPPD crystals. However, HA crystals did serve as effective traps for PPi-4 ions and their presence led to more stable CPPD crystal growth.

Suppression of active collagenase from calcified lapine synovium by Arteparon.

Collagenase has been implicated in the pathogenesis of several arthropathies. Arteparon [glycos-aminoglycan (GAG) polysulfate] is a proteinase inhibitor that is being investigated as a therapeutic agent in osteoarthritis. We found that cultures of calcified lapine synovium release collagenase, one tenth of which is already activated. Normal synovium produces no active collagenase. GAG polysulfate suppresses the amount of active collagenase by one half. GAG polysulfate may interfere with the activation process of collagenase.

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.