Molecular Dynamics Simulation of Crystal-Induced Membranolysis

Wierzbicki, Andrzej; Dalal, Pranav; Madura, Jeffry D.; Cheung, Herman S.

doi:10.1021/jp0305988

Cited by 17 publications

(21 citation statements)

References 42 publications

(72 reference statements)

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“…They identified that the [010] crystal surface of CPPD is responsible for the interaction with the phospholipid bilayer, which leads to crystal-induced membranolysis. The process is very similar to the lysis induced by melittin in bee and snake venom [46]. It is interesting to note that when the same [010] CPPD crystal surface binds to an anticalcification agent such as phosphocitrate, it leads to the retardation of crystal growth and cessation of crystal growth [47].…”

Section: Crystal-induced Inflammatory Responsementioning

confidence: 84%

“…So far, the molecular mechanism of crystal-induced membranolysis is still unclear. Using the molecular dynamics simulations of the phospholipid bilayer-CPPD crystal to determine how the interactions between the bilayer and the crystal affect the dynamics and stability of the phospholipid bilayer, Wierzbicki et al [46] reported that the interactions between the surface of CPPD and the extracellular layer of the hydrated dimyristoyl phosphatidylcholine phospholipid bilayer may lead to decoupling of the external layer from the intracellular side of the membrane. In turn, a local thinning of the layer on the intracellular side of the membrane occurs, which favors water penetration leading to membranolysis.…”

Section: Crystal-induced Inflammatory Responsementioning

confidence: 99%

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Biologic effects of calcium-containing crystals

Cheung

2005

Current Opinion in Rheumatology

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Evidence for a causal role of crystals in cartilage degeneration in osteoarthritis is primarily inferential and is based on correlative data. Clinical observations indicate that exaggerated and uniquely distributed cartilage degeneration is associated with these deposits. Measurements of putative markers of cartilage breakdown suggest that these crystals magnify the degenerative process. Studies have shown two potential mechanisms by which crystals cause degeneration. These involve the stimulation of mitogenesis in synovial fibroblasts and the secretion of metalloproteinases by cells that subject these crystals to phagocytosis. New information on how crystals form and how they exert their biologic effects will help in the design of an effective therapeutic approach.

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Section: Crystal-induced Inflammatory Responsementioning

confidence: 84%

Section: Crystal-induced Inflammatory Responsementioning

confidence: 99%

Biologic effects of calcium-containing crystals

Cheung

2005

Current Opinion in Rheumatology

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“…Inflammation in the inflammatory diseases such as arthritis is proposed to be due to the rupture of the lysosome phospholipid membrane and the release of lysosomal enzymes into the cytoplasm. The rupture of the membrane or membranolysis is usually accompanied by the crystal deposition near the membrane (1)(2)(3)(4). Calcium pyrophosphate dihydrate (CPPD) crystal is one of the most common forms of pathologic articular mineral, and its deposition leads to pseudogout, an inflammatory disease.…”

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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“…PC specifically inhibits crystal‐induced MMP synthesis and mitogenesis in cells, while it has no effect on similar processes induced by growth factors or serum (7, 13, 16–18). This blocking effect is likely explained by the influence of PC on the interaction of calcium crystals with biomembranes (19–22). PC is a potent in vitro inhibitor of hydroxyapatite crystal formation (23).…”

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confidence: 99%

Phosphocitrate blocks calcification‐induced articular joint degeneration in a guinea pig model

Cheung¹,

Sallis²,

Demadis³

et al. 2006

Arthritis & Rheumatism

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Objective. Calcium deposition occurs frequently in osteoarthritic (OA) joints. However, evidence for a causal role of calcification in cartilage degeneration is inferential. The present study was undertaken to examine the role of calcification in OA disease progression and to evaluate a formulation of phosphocitrate (PC) as a potential therapeutic agent.Methods. We have identified a guinea pig OA model in which meniscal calcification appears to correlate with aging and disease progression. We synthesized a new formulation of PC, [CaNa(PC) 2 (H 2 O)] n (CaNaPC), which is a potent antimineralization agent and a specific inhibitor of crystal-induced biologic effects. After weekly treatment of guinea pigs with experimental OA with CaNaPC for 3 months, we examined calcification in menisci and cartilage degeneration. As a control, we examined whether similar CaNaPC treatment had any therapeutic effect in a hemi-meniscectomy model in which there is no known crystal involvement.Results. Meniscal calcification correlated with cartilage degeneration in this animal model. PC treatment led to significant reduction of calcium deposits and arrested OA disease progression. Similar treatment had no effect in the hemi-meniscectomy model.Conclusion. CaNaPC diminishes mineralization in a cutaneous calcergy model and a model of OA in which intraarticular mineralization is a prominent feature. In the OA guinea pig model, inhibition of calcification is accompanied by diminished cartilage degeneration. CaNaPC has no therapeutic effect in the hemimeniscectomy model. We conclude that pathologic calcification may initiate or amplify processes leading to cartilage degeneration and that CaNaPC may interrupt such a pathway.

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Molecular Dynamics Simulation of Crystal-Induced Membranolysis

Cited by 17 publications

References 42 publications

Biologic effects of calcium-containing crystals

Biologic effects of calcium-containing crystals

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

Phosphocitrate blocks calcification‐induced articular joint degeneration in a guinea pig model

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