Cartilage nucleoside triphosphate pyrophosphohydrolase. II. role in extracellular pyrophosphate generation and nucleotide metabolism

Ryan, Lawrence M.; Wortmann, Robert L.; Karas, Barbara; McCarty, Daniel J.

doi:10.1002/art.1780280409

Cited by 31 publications

(12 citation statements)

References 24 publications

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“…This study therefore accords with previous reports in showing (a) higher synovial fluid PPi concentrations and NTPase activities in pyrophosphate arthropathy than in osteoarthritis and (b) lower values in rheumatoid arthritis than in pyrophosphate arthropathy or osteoarthritis. For example, Rachow et al,35 using the radiometric method of Cheung and Suhadolnik,'9 found significant differences in PPi concentrations in synovial fluid from various joints (knees, shoulders, hips) of 40 patients with osteoarthritis and 27 with pyrophosphate arthropathy (mean (SD) 14 (5) and 18 (8) [imol/I respectively); correspondingly higher NTPase activity was found in pyrophosphate arthropathy. Silcox and McCarty, using a differential colorimetric method, measured synovial fluid PPi in 35 patients with osteoarthritis, 29 with pyrophosphate arthropathy, and 12 with rheumatoid arthritis and found mean (range) concentrations of 9-2 (3-35), (4-24), and 4-2 (2-8) [imol/l respectively8; the differences between rheumatoid arthritis and both osteoarthritis and pyrophosphate arthropathy were significant (Student's t test).…”

Section: Resultsmentioning

confidence: 99%

Synovial fluid pyrophosphate and nucleoside triphosphate pyrophosphatase: comparison between normal and diseased and between inflamed and non-inflamed joints.

Pattrick

Hamilton

Hornby

et al. 1991

Annals of the Rheumatic Diseases

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Section: Resultsmentioning

confidence: 99%

Synovial fluid pyrophosphate and nucleoside triphosphate pyrophosphatase: comparison between normal and diseased and between inflamed and non-inflamed joints.

Pattrick

Hamilton

Hornby

et al. 1991

Annals of the Rheumatic Diseases

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“…ePPi can be generated from eATP through the action of ecto-enzymes with nucleoside triphosphate pyrophosphohydrolase (NTPPPH) activity, such as ENPP1. Because there is ample ENPP1 activity in normal cartilage to convert all available NTP to NMP and PPi, substrate availability is the rate-limiting step in this reaction [11]. We recently demonstrated that chondrocyte eATP and ePPi elaboration were coordinately regulated [8], supporting a major role for eATP in ePPi production by cartilage.…”

Section: Introductionmentioning

confidence: 99%

The progressive ankylosis gene product ANK regulates extracellular ATP levels in primary articular chondrocytes

et al. 2013

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IntroductionExtracellular ATP (eATP) is released by articular chondrocytes under physiological and pathological conditions. High eATP levels cause pathologic calcification, damage cartilage, and mediate pain. We recently showed that stable over-expression of the progressive ankylosis gene product, ANK, increased chondrocyte eATP levels, but the mechanisms of this effect remained unexplored. The purpose of this work was to further investigate mechanisms of eATP efflux in primary articular chondrocytes and to better define the role of ANK in this process.MethodsWe measured eATP levels using a bioluminescence-based assay in adult porcine articular chondrocyte media with or without a 10 minute exposure to hypotonic stress. siRNAs for known ATP membrane transporters and pharmacologic inhibitors of ATP egress pathways were used to identify participants involved in chondrocyte eATP release.ResultseATP levels increased after exposure to hypotonic media in a calcium-dependent manner in monolayer and 3-dimensional agarose gel cultures (p < 0.001). A potent transient receptor potential vanilloid 4 (TRPV4) agonist mimicked the effects of hypotonic media. ANK siRNA suppressed basal (p < 0.01) and hypotonically-stressed (p < 0.001) ATP levels. This effect was not mediated by altered extracellular pyrophosphate (ePPi) levels, and was mimicked by the ANK inhibitor, probenecid (p < 0.001). The P2X7/4 receptor inhibitor Brilliant Blue G also suppressed eATP efflux induced by hypotonic media (p < 0.001), while ivermectin, a P2X4 receptor stimulant, increased eATP levels (p < 0.001). Pharmacologic inhibitors of hemichannels, maxianion channels and other volume-sensitive eATP efflux pathways did not suppress eATP levels.ConclusionsThese findings implicate ANK and P2X7/4 receptors in chondrocyte eATP efflux. Understanding the mechanisms of eATP efflux may result in novel therapies for calcium crystal arthritis and osteoarthritis.

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“…For instance, the release of cartilage breakdown products (10,20) and crystals, which include calcium pyrophosphate dihydrate and apatite crystals (21)(22)(23), could play an important role. These particles will eventually be phagocytosed by synovial cells and initia.te an inflammatory reaction.…”

Section: Discussionmentioning

confidence: 99%

Neutral proteases in human osteoarthritic synovium

Martel‐Pelletier

Cloutier

Pelletier

1986

Arthritis & Rheumatism

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The activities of neutral collagenolytic enyzmes (CE) and neutral proteoglycan-degrading enzymes (PE) in the synovial membranes of osteoarthritis (OA) patients were determined. The total neutral m e t a l b C E activily showed a significantly higher level of activity when the membranes of OA patients were compared with those of controls. The severely and moderately inflamled synovia had significantly more enzyme activity than (did either mildly inflamed or control synovia. Steroilds reduced the total metallc4E activity. In specimens with severe inflammation, the active form of the neutral metalla-CE was significantly elevated over that found in controls. The serine-CE activity was also significantly elevated in OA synovia with severe inflammation and synovial hypertrophy. The total and active neutral1 m e t a l b P E was significantly elevated in synovial membranes of OA patients with severe inflammation. Moreover, the serine-PE showed much more activity in OA patients than in controls. The enzyme activity remained at a significantly high level in the OA synovium, regardless of the presence or absence of macroscopic synovial hypertrophy or the histologic grading of the synovium (mild, moderate, severe). Our data indicate that, in OA, an increased level of neutral proteases in the synovia could be involved in the local tissue destruction of the periarticular structures. Because of the very high level of seriae proteases, their diffusion may render plausible a degradative action on the cartilage surface.The synovial membrane is a major component of all diarthrodial joints. This tissue has a superficial cell lining, composed of synoviocytes which overlie a subsynovial loose connective tissue. Synovial membranes from patients with inflammatory joint diseases, such as rheumatoid arthritis, show marked synovial lining cell hyperplasia and mixed cellular infiltration, consisting of both mononuclear cells and polymorphonuclear leukocytes (1). The release of proteolytic enzymes from the pannus (2-4) may be responsible, in part, for the cartilage erosion and the disruption of the tendon and ligament integrity.Osteoarthritis patients who have undergone either total knee or total hip replacement are often found to have a prominent inflammatory synovitis that may resemble the inflammatory changes seen in rheumatoid arthritis (5). The synovial membrane shows a lining cell hyperplasia and an inflammatory cellular infiltrate, composed mainly of mononuclear cells. mal and osteoarthritic synovia can produce collagenase, as well as other metalloproteases, in a latent form (6-8). However, there has been no clear evidence osteoarthritic synovium. If there is such an increased level, it could be of major importance, because it of any increased level of neutral proteases within the

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Cartilage nucleoside triphosphate pyrophosphohydrolase. II. role in extracellular pyrophosphate generation and nucleotide metabolism

Cited by 31 publications

References 24 publications

Synovial fluid pyrophosphate and nucleoside triphosphate pyrophosphatase: comparison between normal and diseased and between inflamed and non-inflamed joints.

Synovial fluid pyrophosphate and nucleoside triphosphate pyrophosphatase: comparison between normal and diseased and between inflamed and non-inflamed joints.

The progressive ankylosis gene product ANK regulates extracellular ATP levels in primary articular chondrocytes

Neutral proteases in human osteoarthritic synovium

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