The role of crystals in articular tissue degeneration

Cheung, Herman S.

doi:10.1007/s11926-999-0009-1

Cited by 6 publications

(3 citation statements)

References 38 publications

(28 reference statements)

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“…These effects are hypothesized to be correlated with calcium deposition disease in vivo. The increased production of matrix-degrading MMPs by synoviocytes results in articular damage and degeneration and the release of additional crystals from the surrounding tissue, whereas mitogenesis leads to an increase in synoviocytes that generate more MMPs (37). Of interest are the signal transduction mechanisms by which crystal-induced up-regulation of MMP synthesis and secretion and increased mitogenesis are mediated.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism of the Induction of Metalloproteinases 1 and 3 in Human Fibroblasts by Basic Calcium Phosphate Crystals

Reuben

Brogley

Sun

et al. 2002

Journal of Biological Chemistry

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Calcium-containing crystals such as basic calcium phosphate (BCP) 1 and calcium pyrophosphate dihydrate (CPPD) are two of the most common forms of pathologic articular materials that are associated with destructive arthropathies involving cartilage degeneration (1, 2). At concentrations found in pathologic human joint fluids, these crystals exert biological effects on cultured cells in a manner similar to growth factors like platelet-derived growth factor, epidermal growth factor, and serum. It has been demonstrated that BCP crystals stimulate fibroblast, synoviocyte, and chondrocyte mitogenesis in vitro (3); stimulate the production of prostaglandin via the phospholipase A 2 /cyclo-oxygenase pathway (4); activate phospholipase C and inositol phospholipid hydrolysis (5); induce the expression of the proto-oncogenes, c-fos and c-myc (6, 7); and induce the synthesis and secretion of metalloproteinases (MMPs) 1, 3, 8, and 13 (8 -12).In contrast to other mitogenic and growth factors, BCP crystal-elicited signal transduction pathways have not been completely studied. However, we have identified some of the component molecules involved in calcium-containing crystal signal transduction mechanisms. One pathway activated upon crystal stimulation of human fibroblasts (HF) is the p44 and p42 mitogen-activated protein kinase (p44/42 MAPK) pathway, also known as extracellular signal-related mitogen protein kinases 1 and 2 (ERK1 and ERK2), respectively. The MAPK cascade can be blocked by the selective inhibitors, PD98059 (13) and U0126 (14), which hinder the activation and phosphorylation of MEK (MAPK/ERK kinase). Co-treatment of HF with BCP crystals and PD98059 blocks crystal-induced p44/42 MAPK activation and mitogenesis (15) in addition to crystalinduced up-regulation of MMP-1 and MMP-3 mRNA and protein expressions (16). Moreover, phosphocitrate (PC), a specific inhibitor of the biological effects of BCP and CPPD crystals (17), also blocks crystal-induced activation of p44/42 MAPK, further supporting the role of this signal pathway in crystalinduced responses in HF (15).Another messenger with an apparent role in crystal-activated signal transduction is calcium. We have previously shown that treatment of HF with BCP crystals induces a rapid transient rise of intracellular calcium levels in seconds due to calcium influx from outside the cell, followed by a slow and sustained increase of intracellular calcium within 60 min after stimulation, due to crystal dissolution (18). Removal of calcium from the cell culture medium attenuates the BCP crystal in-

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Section: Discussionmentioning

confidence: 99%

Molecular Mechanism of the Induction of Metalloproteinases 1 and 3 in Human Fibroblasts by Basic Calcium Phosphate Crystals

Reuben

Brogley

Sun

et al. 2002

Journal of Biological Chemistry

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“…114,115 BCP, and to some extent CPPD, crystals induce mitogenesis, stimulate production of prostaglandin E2 (PGE2), activate phospholipase C, promote the synthesis of metalloproteinases (MMPs), and induce proto-oncogenes c-fos and c-myc. [116][117][118] Induction of MMP-1 (collagenase) and MMP-3 (stromelysin) is dependent upon the p42/44 mitogenactivated protein kinase (MAPK) signal transduction pathway.…”

Section: Additional Observationsmentioning

confidence: 99%

Crystal-induced inflammation of the kidneys: results from human studies, animal models, and tissue-culture studies

2004

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Calcium oxalate (CaOx), calcium phosphate (CaP), and uric acid or urate are the most common crystals seen in the kidneys. Most of the crystals evoke an inflammatory response leading to fibrosis, loss of nephrons, and eventually to chronic renal failure. Of the three, CaOx monohydrate is the most reactive, whereas some forms of CaP do not evoke any discernible response. Reactive oxygen species are produced during the interactions between the crystals and renal cells and are responsible for the various cellular responses. CaOx crystals generally form in the renal tubules. Exposure of renal epithelial cells to CaOx crystals results in the increased synthesis of osteopontin, bikunin, heparan sulfate, monocyte chemoattractant protein 1 (MCP-1), and prostaglandin (PG) E2, which are known to participate in inflammatory processes and in extracellular matrix production. CaOx crystal deposition in rat kidneys also activates the renin-angiotensin system. Both Ox and CaOx crystals selectively activate p38 mitogen-activated protein kinase (MAPK) in exposed tubular cells. CaP crystals can form in the tubular lumen, tubular cells, or tubular basement membrane. Renal epithelial cells exposed to brushite crystals produce MCP-1. Basic CaP and calcium pyrophosphate dihydrate induce mitogenesis in fibroblasts, stimulate production of PGE2, and up-regulate the synthesis of metalloproteinases (MMP) while down-regulating the production of inhibitors of MMPs through activation of p42/44 MAPK. Deposition of urate crystals in the kidneys becomes associated with renal tubular atrophy, interstitial fibrosis, and development of inflammatory infiltrate. Renal epithelial cells exposed to uric acid crystals synthesize MCP-1 as well as PGE2. Monocytes or neutrophils exposed to urate crystals produce tumor necrosis factor alpha, interleukin-1 (IL-1), IL-6, and IL-8. Expression of IL-8 is mediated through extracellular signal-regulated kinase 1 (ERK-1)/ERK-2 and nuclear transcription factors activated protein 1 and nuclear factor kappabeta. Urate crystals also stimulate the macrophages to produce MMPs.

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“…15,39 The role of IL-1 in OA is discussed in greater detail below. Additional cytokines, such as tumor necrosis factor (TNF), IL-17, IL-18, oncostatin M, 18,40,41 as well as certain C-X-C and C-C chemokines, 42,43 fibronectin fragments, 44 crystals 45 and glycation end products 46 are additional agents that activate articular chondrocytes, but their roles in OA are ill defined. Importantly, several of these stimuli also suppress compensatory repair synthesis of matrix macromolecules by chondrocytes.…”

Section: Clinical Presentation and Pathophysiology Of Human Oamentioning

confidence: 99%