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PubMed1982

Calcium phosphate deposition disease in great danes.

A new clinicopathologic syndrome, possibly familial, in Great Dane dogs, resembles the familial childhood variant of calcium pyrophosphate dihydrate deposit disease in man, except that the mineral deposits were composed of amorphous calcium phosphate or hydroxyapatite rather than pyrophosphate. The syndrome was characterized clinically by paraplegia and incoordination in very young puppies which was caused by concentric constriction of the posterior cervical spinal cord. Canal stenosis resulted from dorsal displacement of the seventh cervical vertebra and deformation of the vertebral articular processes. Mineral deposition in the diarthrodial joints of the axial skeleton could be seen on radiographs of weanling puppies, and the appendicular skeleton became involved as the dogs matured. Periarticular mineralization of the limbs was associated with shorter bones, a thin cortex, abnormal bone curvature, and increased medullary trabeculae. Bone alterations were associated with abnormalities of the growth plate, which had focal areas of cartilage calcification. Soft tissue mineralization, seen in all dogs, was a primary feature of the disease process. Serum calcium concentrations were within the normal range, but serum phosphorus concentrations were decreased.

Animals↗

PubMed1976

The histochemical demonstration of calcium with 8-hydroxyquinoline.

A method for the histochemical demonstration of calcium using 8-hydroxyquinoline was investigated. It was found to give intense, highly selective staining of various pathologic and natural calcifications, and compared favourably with conventional procedures for calcium. Calcium oxalate and calcium pyrophosphate were not stained.

Calcium↗

PubMed1991

Inorganic pyrophosphate, nucleoside triphosphate pyrophosphatase, and cartilage fragments in normal human synovial fluid.

The association between calcium pyrophosphate dihydrate (CPPD) crystal deposition and ageing is unexplained. Levels of inorganic pyrophosphate (PPi) and activity of nucleoside triphosphate pyrophosphatase (NTPP) were estimated in synovial fluid from 91 asymptomatic normal knees, including five with isolated CPPD crystal deposition (70 subjects; median age 47, range 22-83 years). In non-crystal fluids, PPi levels and NTPP activities were low (median, interquartile range: 9.5, 7.6-12.3 microM, and 1, 0.4-2 microM/30 min/mg protein, respectively: n = 50) and a generalized increase with age was not demonstrated. Higher values for PPi and NTPP in all five subjects with isolated CPPD deposition supports involvement of altered PPi metabolism, unrelated to ageing per se, in crystal formation. Presumed cartilage fragments were identified by morphological characteristics in 70% of normal fluids: metachromatic staining and electron microscopy, undertaken in a limited number, supported identification of such particles as cartilage. This finding supports dynamic turnover of healthy matrix, and questions the usefulness of identification, without quantification, cartilage fragments as a measure of cartilage damage.

Adult↗

PubMed1996

Prevalence and possible pathological significance of calcium phosphate salt accumulation in tendon matrix degeneration.

OBJECTIVES: To investigate the prevalence of calcium phosphate mineral salt accumulation in degenerative supraspinatus 'tendinitis' compared with a normal sample of human tendons, and to determine whether there is an association of calcium salt deposition with pathological changes in the tendon extracellular matrix. METHODS: Cadaver tendons (supraspinatus and common biceps tendons, n = 96) and fragments of supraspinatus tendons obtained during shoulder surgery (n = 31) were analysed for calcium content by atomic absorption spectroscopy, phosphorous content using a spectrophotometric assay, and matrix composition (collagen, glycosaminoglycans and DNA) using standard biochemical techniques. RESULTS: We established baseline values of calcium concentration in macroscopically normal cadaver tendons (mean 1.1 (SD 0.35) micrograms/mg dry wt, n = 60) and found that 33% (nine of 27) of ruptured tendons from patients with 'degenerative tendinitis' contained an excess of calcium (more than 2SD greater than the normal sample mean). Five of these specimens had increased concentrations of phosphorous and calcium:phosphorous (molar) ratios consistent with a variety of possible calcium crystals, including calcium pyrophosphate, hydroxyapatite, and tricalcium phosphate, in addition to mixed or amorphous calcium phosphate deposits. Four of these specimens contained normal concentrations of phosphorous, consistent with deposits of calcium oxalate or calcium carbonate, although this was not confirmed biochemically. In contrast, surgical specimens (n = 4) from patients with 'calcifying tendinitis' (radiographically detected calcium deposits) all contained salts with a mineral composition consistent with hydroxyapatite. The presence and identity of crystal deposits was subsequently confirmed in five specimens by radiographic microanalysis. Analysis of the tendon matrix demonstrated a number of significant differences between normal and degenerate (ruptured) tendons, including a reduction in collagen content, an increase in sulphated glycosaminoglycans (predominantly dermatan sulphate) and an increase in DNA (cellular) content. However, there were no significant differences between degenerate tendons that were 'calcified' and those degenerate specimens that contained normal concentrations of calcium. CONCLUSIONS: Although there was a relatively high prevalence of calcium salts in degenerate tendons, which might contribute to the pathological process (such as increased matrix collagen degradation), these data are consistent with the hypothesis that 'dystrophic calcification' of degenerate tendon matrix is a pathological entity distinct from cell mediated 'calcifying tendinitis'. Calcification is probably one possible outcome (or end point) of chronic tendon injury, although the possibility exists that in many cases, the presence of calcium salts may contribute to the tendon matrix degeneration.

Adolescent↗

PubMed1994

Ageing increases growth factor-induced inorganic pyrophosphate elaboration by articular cartilage.

Advanced age is the most common risk factor for the development of calcium pyrophosphate dihydrate (CPPD) crystal-associated arthritis. However, the link between ageing and CPPD crystal formation in cartilage remains unexplained. In CPPD deposition disease, excess extracellular inorganic pyrophosphate (ePPi), generated by articular chondrocytes, accumulates in affected joints and contributes to CPPD crystallogenesis. Transforming growth factor beta 1 (TGF beta 1) is the first known physiologic stimulant of ePPi elaboration by adult porcine and human cartilage. We hypothesized that sensitivity of articular cartilage to the ePPi-stimulatory effects of TGF beta 1 may increase with ageing. Accordingly, we compared the effects of TGF beta 1 on cartilage ePPi elaboration from juvenile, young adult, and old adult pigs. Cartilage organ cultures from old animals increased ePPi elaboration in response to TGF beta 1 to a greater extent than did cartilage from juvenile and young adult animals. Similar results were seen in chondrocyte monolayers. Concurrent exposure to epidermal growth factor (EGF) augmented, but was not necessary for TGF beta 1-induced ePPi elaboration by adult cartilage. In contrast, in juvenile cartilage, concurrent exposure to EGF was required to permit TGF beta 1-induced ePPi elaboration. Thus, increased cartilage responsiveness to the ePPi-stimulatory effects of TGF beta 1 occurs with ageing, and may explain the link between advanced age and CPPD deposition disease.

Aging↗

PubMed2005

Calcium-containing crystals and osteoarthritis: implications for the clinician.

The clinical implication of articular deposits of calcium-containing crystals (specifically of calcium pyrophosphate dihydrate and hydroxyapatite) in osteoarthritis is unknown. Recent longitudinal studies have suggested that in some instances calcium crystals are direct participants in cartilage damage, while in other situations they are merely markers of joint damage. Better understanding of the mechanisms of crystal formation, especially in relation to inorganic pyrophosphate regulation, has lead to potential avenues for therapeutic intervention. The current treatment of osteoarthritis associated with calcium-containing crystals should involve nonsteroidal anti-inflammatory drugs, intra-articular steroids, and in resistant cases, joint irrigation can be considered. While preliminary studies suggest the possibility of favorable benefits from colchicine and hydroxycholorquine in this osteoarthritis disease subset, more rigorous studies need to be conducted to establish their roles.

Antirheumatic Agents↗

PubMed1994

Submicroscopic crystals in osteoarthritic synovial fluids.

OBJECTIVES: To investigate the hypothesis that synovial fluid (SF) from patients with osteoarthritis (OA) may contain calcium phosphate crystals that are either too small, or too few in number to be identified by conventional light microscopy techniques. METHODS: Twelve SF from 11 patients with established knee OA, five SF from patients with rheumatoid arthritis (RA), and two control samples of SF from patients with pseudogout were subjected to an enzyme/hypochlorite extraction procedure. The patients with OA and RA had no radiographic evidence of chondrocalcinosis, or SF crystals on polarised light microscopy. Extracted material was examined and analysed by analytical electron microscopy (AEM) and x ray powder diffraction (XRD). RESULTS: Mineral was found in 11 of 12 OA samples, ranging from 2-120 micrograms/ml SF. Analytical electron microscopy revealed calcium pyrophosphate dihydrate (CPPD) crystals in five (confirmed by XRD in three) and basic calcium phosphates (BCP) in eight (five on XRD). Two samples with confirmed CPPD contained some rods with a mean length below 100 nm. The majority of BCP clusters were also less than 100 nm in diameter. BCP was detected in 1/5 RA samples. Control samples contained CPPD crystals of the expected size range of 0.42-17.9 microns. CONCLUSIONS: The data indicate that many OA SF may contain CPPD or BCP crystals which are too small or too few in number to be identified by conventional techniques. Crystal deposition is not an 'on-off' phenomenon in OA.

Aged↗

PubMed2003

Preparation and osteocompatibility of hydroxyapatite coated on titanium from the reaction of sputtered CaO and vaporized P2O5.

Hydroxyapatite (HA) and other calcium phosphates were synthesized on titanium plates by a solid-gas state reaction of sputtered CaO and vaporized P(2)O(5). The calcium phosphates formed were HA, beta-tricalcium phosphate (beta-TCP; Ca(3)(PO(4))(2)), beta-calcium pyrophosphate (beta-PYR; Ca(2)P(2)O(7)), and beta-calcium metaphosphate (beta-MET; Ca(2)(PO(3))(2)). Their formation depended on the ratio of the sputtered CaO and the reacting P(2)O(5). For a mole ratio of CaO/P(2)O(5)=4 (Ca/P=2), an HA film was synthesized. The surface roughness increased by over seven times after the solid-gas state reaction from Ra = 0.16+/-0.02 microm (for the CaO film) to Ra = 1.15+/-0.25 microm (for the reacted film). The synthesized HA film-coated titanium plates and control non-coated titanium plates were implanted in the femora of two dogs for a period of two, four and 12 weeks, and observed using a soft X-ray radiograph and histological sections. New bone formation was observed without any connective tissue at four weeks around the HA film, whereas over the 12 week experimental period, there was no new bone formation around the control and connective tissue was observed over all periods, reaching a thickness of more than 200 microm at 12 weeks.

Animals↗

PubMed2006

Osteoblast response to zirconia-hybridized pyrophosphate-stabilized amorphous calcium phosphate.

Calcium phosphate bioceramics, such as hydroxyapatite, have long been used as bone substitutes because of their proven biocompatibility and bone binding properties in vivo. Recently, a zirconia-hybridized pyrophosphate-stabilized amorphous calcium phosphate (Zr-ACP) has been synthesized, which is more soluble than hydroxyapatite and allows for controlled release of calcium and phosphate ions. These ions have been postulated to increase osteoblast differentiation and mineralization in vitro. The focus of this work is to elucidate the physicochemical properties of Zr-ACP and to measure cell response to Zr-ACP in vitro using a MC3T3-E1 mouse calvarial-derived osteoprogenitor cell line. Cells were cultured in osteogenic medium and mineral was added to culture at different stages in cell maturation. Culture in the presence of Zr-ACP showed significant increases in cell proliferation, alkaline phosphatase activity (ALP), and osteopontin (OPN) synthesis, whereas collagen synthesis was unaffected. In addition, calcium and phosphate ion concentrations and medium pH were found to transiently increase with the addition of Zr-ACP, and are hypothesized to be responsible for the osteogenic effect of Zr-ACP.

Animals↗

PubMed1989

Hydroxyapatite associated disease in an elderly female: differentiation from aseptic necrosis.

The crystal arthropathies caused by monosodium urate and calcium pyrophosphate dihydrate are commonly recognised, but the destructive arthropathy associated with the deposition of calcium hydroxy-apatite is less well known in general clinical practice. We describe a case with many of the classical features of hydroxy-apatite associated disease and discuss the features differentiating the condition from aseptic necrosis.

Aged↗

PubMed1981

Increased pyrophosphate in fibroblasts and lymphoblasts from patients with hereditary diffuse articular chondrocalcinosis.

The metabolic and genetic factors leading to deposition of calcium pyrophosphate crystals in cartilage of patients with chondrocalcinosis are not well understood. Analysis of cultured fibroblasts and lymphoblasts from 12 affected members of a large kindred showed a mean concentration of intracellular inorganic pyrophosphate two times greater than that in cells from unaffected family members or normal, unrelated volunteers. Increased intracellular pyrophosphate may, therefore, be a biochemical marker for the heterozygous expression of the chondrocalcinosis gene.

Cells, Cultured↗

PubMed1984

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↗

PubMed1991

Transforming growth factor beta 1 stimulates inorganic pyrophosphate elaboration by porcine cartilage.

The overproduction of inorganic pyrophosphate (PPi) by cartilage is thought to be a key element in the formation of calcium pyrophosphate dihydrate (CPPD) crystals in joints, and the subsequent development of pseudogout or chondrocalcinosis. We report herein that transforming growth factor beta 1 (TGF beta 1), alone and in synergy with epidermal growth factor (EGF) or TGF alpha, markedly stimulates PPi elaboration by porcine articular cartilage in organ culture and monolayer culture. This effect is not seen with platelet-derived growth factor, basic fibroblast growth factor, or insulin-like growth factor types 1 and 2, substances which also affect chondrocyte metabolism or are mitogenic. TGF beta 1 produces only a modest increase in nucleoside triphosphate pyrophosphohydrolase (NTPPPH), a chondrocyte ectoenzyme that produces PPi; this implies the existence of other pathways for PPi elaboration. TGF beta 1 is present in joint fluid and cartilage. TGF beta 1, TGF alpha, and EGF are the first known physiologic modifiers of cartilage PPi production. They provide a novel model for the study of CPPD crystal formation in cartilage, as well as new insights into the pathogenesis of this common affliction of aging.

Animals↗

PubMed2001

[Familial articular chondrocalcinosis: study of an Alsatian family].

Familial articular chondrocalcinosis is a chronic articular disease characterized by acute intermittent attacks of arthritis, presence of calcium pyrophosphate dihydrate crystal in synovial fluid, cartilage and periarticular soft tissue and by x rays calcium deposition in articular cartilage. A family originating from Alsace, with an autosomal dominant transmission has been studied. As in English and Argentinean families, a linkage to the short arm of chromosome 5p has been found. These results suggest that a defective gene at this location may be related to the chondrocalcinosis in these families.

Adult↗

PubMed1989

Augmentation of inorganic pyrophosphate elaboration in cartilage by serum factors.

The disordered production of inorganic pyrophosphate (PPi) by articular cartilage is thought to have an important role in the pathogenesis of calcium pyrophosphate dihydrate deposition disease and perhaps osteoarthritis. We have previously shown that fetal calf serum added to the culture media of porcine articular cartilage explants increases the elaboration of PPi into the ambient media. We have examined this PPi stimulatory activity by studying the effects of adult human serum (HS), serum derived from adult human plasma (HP), and an acid-alcohol extract of human platelets (PE) on PPi production in cartilage organ culture. Ten percent HS produces a 1.4-fold increase in PPi production after 48 h of culture, while cartilage incubated in media containing 10% HP produces no more PPi than that incubated in media alone. PE stimulates a mean 2-fold increase in PPi production at 48 h in the presence of low concentrations of HP, and has no effect alone. It does not appear to up-regulate the activity of the ectoenzyme nucleoside triphosphate pyrophosphohydrolase (NTPPPH), nor does it promote the release of enzyme substrate into the extracellular space. Cartilage exposed to 0.5% HP and PE has 1.51 +/- 0.36 units of NTPPPH activity whereas cartilage exposed to 0.5% HP alone has 1.52 +/- 0.41 units of enzyme activity. PE does not increase the release of [14C]adenine-labeled compounds into the media. Approximately 13% of soluble 14C counts was found in the media of chondrocytes treated with PE while 18% of counts was released in the presence of HP alone. We have demonstrated a factor or factors present in FCS, HS, and an acid-ethanol extract of human platelets which represent(s) the first known physiologic modulators of PPi production in articular cartilage and may increase PPi production without affecting NTPPPH activity.

Adenine↗

PubMed2006

P5L mutation in Ank results in an increase in extracellular inorganic pyrophosphate during proliferation and nonmineralizing hypertrophy in stably transduced ATDC5 cells.

Ank is a multipass transmembrane protein that regulates the cellular transport of inorganic pyrophosphate. In the progressive ankylosis (ank) mouse, a premature termination mutation at glutamic acid 440 results in a phenotype characterized by inappropriate deposition of basic calcium phosphate crystals in skeletal tissues. Mutations in the amino terminus of ANKH, the human homolog of Ank, result in familial calcium pyrophosphate dihydrate deposition disease. It has been hypothesized that these mutations result in a gain-of-function with respect to the elaboration of extracellular inorganic pyrophosphate. To explore this issue in a mineralization-competent system, we stably transduced ATDC5 cells with wild-type Ank as well as with familial chondrocalcinosis-causing Ank mutations. We evaluated the elaboration of inorganic pyrophosphate, the activity of pyrophosphate-modulating enzymes, and the mineralization in the transduced cells. Expression of transduced protein was confirmed by quantitative real-time PCR and by ELISA. Levels of inorganic pyrophosphate were measured, as were the activities of nucleotide pyrophosphatase phosphodiesterase and alkaline phosphatase. We also evaluated the expression of markers of chondrocyte maturation and the nature of the mineralization phase elaborated by transduced cells. The cell line expressing the proline to leucine mutation at position 5 (P5L) consistently displayed higher levels of extracellular inorganic pyrophosphate and higher phosphodiesterase activity than the other transduced lines. During hypertrophy, however, extracellular inorganic pyrophosphate levels were modulated by alkaline phosphatase activity in this cell system, resulting in the deposition of basic calcium phosphate crystals only in all transduced cell lines. Cells overexpressing wild-type Ank displayed a higher level of expression of type X collagen than cells transduced with mutant Ank. Other markers of hypertrophy and terminal differentiation, such as alkaline phosphatase, osteopontin, and runx2, were not significantly different in cells expressing wild-type or mutant Ank in comparison with cells transduced with an empty vector or with untransduced cells. These results suggest that the P5L Ank mutant is capable of demonstrating a gain-of-function with respect to extracellular inorganic pyrophosphate elaboration, but this effect is modified by high levels of expression of alkaline phosphatase in ATDC5 cells during hypertrophy and terminal differentiation, resulting in the deposition of basic calcium phosphate crystals.

Alkaline Phosphatase↗

PubMed1990

Cartilage inorganic pyrophosphate elaboration is independent of sulfated glycosaminoglycan synthesis.

Inorganic pyrophosphate (PPi), a product of glycosaminoglycan synthesis, may be cosecreted with matrix proteoglycan to reach the extracellular site where calcium pyrophosphate dihydrate crystals form. To test this hypothesis, sulfated glycosaminoglycan synthesis by articular cartilage in culture was stimulated or inhibited while the effect on extracellular PPi was measured. When stimulated by 0.8 mM xyloside to increase 35SO4 incorporation (mean +/- SEM % of control 183 +/- 16, n = 5), PPi accumulation changed little (from 54 +/- 6 pmoles/mg to 63 +/- 8 pmoles/mg of cartilage wet weight). Inhibition of sulfation with monensin or diethylcarbamazine disproportionately lowered 35SO4 incorporation compared with PPi elaboration. Using 60 mM diethylcarbamazine, PPi production was preserved (105 +/- 8% mean +/- SEM) compared with control cultures, while sulfation was markedly inhibited (7 +/- 1%). This dissociation of sulfate incorporation and PPi secretion indicates that it is not likely that glycosaminoglycan sulfation is the source of the PPi that escapes from chondrocytes to participate in the formation of extracellular crystals.

Animals↗

PubMed1994

Insulin-like growth factor-1 suppresses pyrophosphate elaboration by transforming growth factor beta1-stimulated chondrocytes and cartilage.

Our objective was to examine the effect of insulin-like growth factor-1 (IGF-1) on extracellular pyrophosphate (ePPi) elaboration by porcine cartilage. These studies further define the factors influencing ePPi accrual, a key step in calcium pyrophosphate dihydrate (CPPD) crystal formation. ePPi was measured in adult porcine organ and monolayer culture media in the presence of IGF-1, transforming growth factor beta-1 (TGFbeta-1), IGF-1 antibody and synovial fluid (SF). As previously shown, TGFbeta-1 stimulated ePPi elaboration by cartilage and chondrocytes. IGF-1 significantly inhibited the stimulatory effect of TGFbeta-1 on ePPi elaboration by both cartilage explants and chondrocytes. Anti-IGF-1 antibody blocked this inhibition. Anti-IGF-1 antibody also decreased the inhibitory effect of SF on ePPi elaboration, suggesting the presence of active IGF-1. These results support an important regulatory role for IGF-1 in cartilage ePPi elaboration. IGF-1 inhibited the effects of the ePPi-stimulatory factor TGFbeta-1 and thus may protect normal joints from excess accumulation of ePPi and subsequent CPPD crystal formation.

Animals↗