Protection of crystal-induced polymorphonuclear leukocyte membranolysis by phosphocitrate

Sallis, John D.; Shankar, Ravi; Rees, Beth; Thomson, R. M.

doi:10.1016/0885-4505(89)90008-x

Cited by 9 publications

(7 citation statements)

References 12 publications

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“…Phosphocitrate (PC) is a powerful calcification inhibitor, which prevents soft tissue calcification, and displays no toxic side effect in rats in doses up to 150 μmol/kg/day . PC also inhibits crystal‐induced cell membrane damages, mitogenesis, expression of extracellular matrix‐degrading enzymes, and crystal‐induced cell death . These findings provided support for the hypothesis that PC is a potentially disease‐modifying drug for calcification‐induced or crystal‐associated OA therapy .…”

mentioning

confidence: 67%

Biological effects and osteoarthritic disease‐modifying activity of small molecule CM‐01

Sun

Roberts

Mauerhan

et al. 2017

Journal Orthopaedic Research

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Phosphocitrate inhibits cartilage degeneration, however, the prospect of phosphocitrate as an oral disease modifying drug might be limited. The purpose of this study was to investigate the biological effects and disease-modifying activity of a phosphocitrate "analog," CM-01 (Carolinas Molecule-01), and test the hypothesis that CM-01 is a disease modifying drug for osteoarthritis therapy. The effects of CM-01 on calcium crystal-induced expression of matrix metalloproteinase-1 and interleukin-1 beta, cell-mediated calcification and production of proteoglycan by chondrocytes were examined in cell cultures. Disease-modifying activity was examined using Hartley guinea pig model of posttraumatic osteoarthritis. Cartilage degeneration in untreated and CM-01 treated guinea pigs was examined with Indian ink and Safranin-O-fast green. Levels of matrix metalloproteinase-13, ADAM metallopeptidase with thrombospondin type 1 motif 5, chemokine (C-C motif) ligand 5, and cyclooxygenase 2 were examined with immunostaining. CM-01 inhibited crystal-induced expression of matrix metalloproteinase-1 and interleukin-1β, reduced cell-mediated calcification, and stimulated the production of proteoglycan by chondrocytes. In Hartley guinea pigs, CM-01 not only reduced damages in articular surface but also reduced resorption of calcified zone cartilage. The reduction in cartilage degeneration was accompanied by decreased levels of matrix metalloproteinase-13, ADAM metallopeptidase with thrombospondin type 1 motif 5, chemokine (C-C motif) ligand 5 and cyclooxygenase 2. These findings confirmed that CM-01 is a promising candidate to be tested as an oral drug for human OA therapy. CM-01 exerted its disease-modifying activity on osteoarthritis, in part, by inhibiting the production of matrix-degrading enzymes and a molecular program resembling the endochondral pathway of ossification. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:309-317, 2018.

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mentioning

confidence: 67%

Biological effects and osteoarthritic disease‐modifying activity of small molecule CM‐01

Sun

Roberts

Mauerhan

et al. 2017

Journal Orthopaedic Research

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“…Understanding these interactions at the molecular level is extremely helpful, not only to elucidate the molecular nature of cell-crystal interaction, but also to aid in design of therapeutic agents that could diminish such an interaction. There is already some experimental evidence that phosphocitrate, a polyanion, protects from crystal-induced polymorphonuclear leukocyte membranolysis (9). The CPPD crystal surface, although neutral, contains loci of both positive and negative charges, and is able to attract complementarily charged molecular species, like the highly negatively charged (ÿ4) phosphocitrate anion.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulation Studies of the Effect of Phosphocitrate on Crystal-Induced Membranolysis

Dalal

Zanotti

Wierzbicki

et al. 2005

Biophysical Journal

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In this study, following our earlier work on calcium pyrophosphate dihydrate (CPPD) crystal-induced membranolysis, we demonstrate, using the CHARMM method of molecular dynamics simulation, the protective role of phosphocitrate (PC) against solvated dimyristoyl phosphatidylcholine phospholipid bilayer disintegration on contact with the CPPD crystal. Our molecular dynamics simulations studies show that coverage of the CPPD crystal with a layer of phosphocitrate molecules results in the conservation of phospholipid bilayer integrity. We show that the rupture of the lipid bilayer in presence of CPPD and the protective effect of PC are primarily due to electrostatic interactions. The protective role of PC, which may also play an important and potentially therapeutic function against crystal-induced membranolysis is also discussed.

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“…There is already some experimental evidence that phosphocitrate, which is a polyanion, protects from crystalinduced polymorphonuclear leukocyte membranolysis. 17 Interestingly, quite advanced theoretical investigations of the rupture of phospholipid bilayers have been undertaken for systems involving lysis of the phospholipid membranes not by inorganic crystal surfaces but by small proteins. For some time now, there has been an intensive effort undertaken to elucidate the membranolysis induced by melittin, which is a small R-helical protein from honey bee venom that is known to rupture cell membranes.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulation of Crystal-Induced Membranolysis

et al. 2003

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Calcium pyrophosphate dihydrate (CPPD) crystals occur frequently in noninflammatory osteoarthritic joints; however, they can be phlogistic and membranolytic, causing acute pseudogout attack. So far, the molecular mechanism of crystal-induced membranolysis is still unclear. In this study, using the method of Chemistry at Harvard Macromolecular Mechanics (CHARMM) molecular dynamics, we show that the interactions between the surface of CPPD crystal and the extracellular layer of the hydrated dimyristoyl phosphatidylcholine (DMPC) phospholipid bilayer may lead to decoupling of the external layer from the intracellular side of the membrane. As a result, a local thinning of the layer on the intracellular side of the membrane occurs, which favors water penetration, leading to membranolysis.

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Protection of crystal-induced polymorphonuclear leukocyte membranolysis by phosphocitrate

Cited by 9 publications

References 12 publications

Biological effects and osteoarthritic disease‐modifying activity of small molecule CM‐01

Biological effects and osteoarthritic disease‐modifying activity of small molecule CM‐01

Molecular Dynamics Simulation Studies of the Effect of Phosphocitrate on Crystal-Induced Membranolysis

Molecular Dynamics Simulation of Crystal-Induced Membranolysis

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