Phosphocitrate Inhibits a Basic Calcium Phosphate and Calcium Pyrophosphate Dihydrate Crystal-induced Mitogen-activated Protein Kinase Cascade Signal Transduction Pathway

Nair, Deepu; Misra, Ravi; Sallis, John D.; Cheung, Herman S.

doi:10.1074/jbc.272.30.18920

Cited by 82 publications

(74 citation statements)

References 29 publications

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“…Various studies reveal that numerous signaling intermediates are activated when cells are treated with calcium crystals including PL-C, PKC α and mµ [26,27], Ras small molecular weight GTPases [5], and the ERK1 and ERK2 members of the mitogen activated protein kinase (MAPK) family [18]. Our experiments indicate activation ERK1/ERK2 mostly occurs through a p21 ras -dependent pathway.…”

Section: Discussionmentioning

confidence: 60%

“…In murine and human fibroblasts BCP crystals activate the ERK subfamily of MAPKs, indicating that ERKs are central regulators of BCP signaling to the nucleus [18,19]. Here we show that a Ras/ERK pathway is primarily responsible for activating the c-fos gene through an SRE/CRE dependent mechanism.…”

mentioning

confidence: 61%

“…Some studies show BCP targets the CREB transcription factor [18] as well as NF-κB. The mechanism by which BCP activates NF-κB has not been characterized, although it appears that PKC is not involved.…”

Section: Discussionmentioning

confidence: 99%

“…We previously showed that BCP can activate ERKs [18,19]. Since members of the Ras family are major upstream regulators of ERK activation we investigated the role of Ras family members in mediating BCP-dependent c-fos activation using dominant negative (DN) forms of Ras, Rac1 and RhoA that act by competitively inhibiting the endogenous GTP-binding proteins for their respective GEFs [23].…”

Section: Bcp Activates C-fos Through a P21 Ras -Dependent Signaling Pmentioning

confidence: 99%

“…Since BCP preferentially activates the ERKs in NIH3T3 cells [18,19], to determine whether activation of ERKs is regulated by a Ras dependent pathway we investigated whether DN-Ras family members could block ERK activation using an HA epitope tagged ERK co-transfected with increasing amounts of DN-Ras family members. Immunocomplex kinase assays using a myelin basic protein derived peptide as a substrate showed in Figure 2 that DN-RasN17 significantly blocks ERK activation.…”

Section: Bcp Activates Erks Through a Ras/mek1/2 Dependent Pathwaymentioning

confidence: 99%

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Basic calcium phosphate crystals activate c-fos expression through a Ras/ERK dependent signaling mechanism

Major¹,

Cheung²,

Misra³

2007

Biochemical and Biophysical Research Communications

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Diseases caused by calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystals occur frequently in osteoarthritic joints. Both crystals induce mitogenesis, metalloproteinase synthesis and secretion by fibroblasts and chondrocytes, promoting degradation of articular tissue. We investigated the mechanism by which BCP activates the c-fos proto-oncogene, which has been shown to activate various matrix metalloproteinases (MMPs). We demonstrate that BCP crystals induce c-fos expression primarily through a Ras/ERK dependent signaling mechanism targeting two highly conserved regulatory binding sites, the serum response element (SRE) and the cAMP response element (CRE). These results establish a calcium crystal induced, calcium/Calmodulin independent, signaling pathway in which BCP crystals activate Ras/MAPK, which can directly target an SRFcontaining transcription factor complex, to induce fibroblasts to secrete metalloproteinases.OA in humans can result from various factors including genetic disposition, joint trauma or joint disuse. A potentially important aspect of articular cartilage and other articular tissue is their tendency to form calcium-containing crystals. Crystalline CPPD and BCP are the two commonest forms of pathologic articular mineral. Each occurs frequently in osteoarthritic joints, and each may be phlogistic, causing acute attacks [1,2].There is compelling in vitro evidence that these crystals engender multiple biological effects promoting joint degeneration, and clinical observations support a relationship to OA [2]. Both crystals stimulate fibroblast, synoviocyte and chondrocyte mitogenesis in vitro [2], stimulate the production of prostaglandin (PGE 2 ) via the phospholipase A 2 /cyclo-oxygenase pathway (ref in The collagenase-1 (MMP1) promoter can be directly regulated by the AP-1 transcriptional activator [5], and AP-1 binding sites are found in all three human collagenase genes implicated in calcium-mediated tissue destruction [6][7][8]. AP-1 consists of a heterodimer of Fos and Jun proteins. Crystal-mediated stimulation dramatically induces Fos leading to collagenase expression suggesting calcium-containing crystals may activate expression of matrix degrading enzymes by directly regulating expression of the c-fos gene [9].

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Section: Discussionmentioning

confidence: 60%

mentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Bcp Activates C-fos Through a P21 Ras -Dependent Signaling Pmentioning

confidence: 99%

Section: Bcp Activates Erks Through a Ras/mek1/2 Dependent Pathwaymentioning

confidence: 99%

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Basic calcium phosphate crystals activate c-fos expression through a Ras/ERK dependent signaling mechanism

Major¹,

Cheung²,

Misra³

2007

Biochemical and Biophysical Research Communications

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Basic calcium phosphate crystal induction of collagenase 1 and stromelysin expression is dependent on a p42/44 mitogen-activated protein kinase signal transduction pathway

Brogley¹,

Cruz²,

Cheung³

1999

J. Cell. Physiol.

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Synovial fluid basic calcium phosphate (BCP) crystals are markers of severe joint degeneration in osteoarthritis. These crystals are mitogenic and induce protooncogene expression and matrix metalloproteinase (MMP) synthesis and secretion in human fibroblasts, effects that are specifically blocked by phosphocitrate (PC). We have recently determined that crystals transduce signals to the nucleus via the activation of the p42 and p44 mitogen-activated protein (MAP) kinases (Nair et al., 1997, J Biol Chem 272:18920-18925). Treatment of human fibroblasts (HF) with BCP induces phosphorylation of p42/44 MAPK, which is inhibited by PC in a dose-dependent manner. Blocking of p42/44 MAPK signal transduction with an inhibitor (PD98059) of MEK1, an upstream activator of MAPKs, reduces crystal-induced p42/44 MAPK activation and significantly inhibits crystal-induced cell proliferation. Based on these findings, we sought to determine the role of the p42/44 MAPK signal transduction pathway in crystal-induced expression of matrix MMPs. We demonstrate suppression of crystal-induced MMPs via the utilization of two different MEK inhibitors: PD98059 and the recently described U0126, a novel inhibitor of MEK1 and MEK2. Treatment of HF with PD98059 blocks the induction of crystal-stimulated collagenase 1 (MMP-1) and stromelysin (MMP-3) expression. PD98059 and PC reduced the level of crystal-induced MMP-1 and MMP-3 mRNA expression to that observed in nonstimulated cells. Likewise, PD98059 treatment of HF blocked the epidermal growth factor (EGF)- and crystal-induced increases in MMP-1 and MMP-3 protein expression and secretion as demonstrated by Western blotting and zymography. Treatment of HF with U0126 inhibits EGF-induced phosphorylation of p42/44 MAPK as well as crystal- and EGF-induced upregulation of MMP-1 mRNA. Additionally, we demonstrate that treatment of HF with BCP, EGF, or PD98059 does not significantly alter levels of gelatinase A (MMP-2) mRNA and protein expression.

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Extracellular signal–regulated kinase 1/extracellular signal–regulated kinase 2 mitogen-activated protein kinase signaling and activation of activator protein 1 and nuclear factor κB transcription factors play central roles in interleukin-8 expression stimulated by monosodium urate monohydrate and calcium pyrophosphate crystals in monocytic cells

Liu

O’Connell

Johnson

et al. 2000

Arthritis & Rheumatism

110

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Objective. Monosodium urate monohydrate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals cause acute gout and pseudogout, respectively. Because acute gout and pseudogout appear to be dependent on interleukin-8 (IL-8)-induced neutrophil in-gress, this study was undertaken to define and compare how MSU and CPPD crystals stimulate IL-8 messenger RNA (mRNA) expression in mononuclear phagocytes. Methods. MSU and CPPD crystal-induced mitogen-activated protein kinase (MAPK) signal trans-duction and IL-8 transcriptional activation were studied in human monocytic cells, using the THP-1 cell line. Results. MSU and CPPD crystals (0.5 mg/ml) induced activation of c-Jun N-terminal kinase, extracel-lular signal-regulated kinase 1 (ERK-1)/ERK-2, and p38 MAPK pathways in THP-1 cells. Activation of the ERK-1/ERK-2 pathway was essential for MSU and CPPD crystal-induced IL-8 mRNA expression, whereas the p38 pathway played a greater role in IL-8 mRNA expression in response to CPPD crystals in comparison with MSU crystals. Both crystals induced the binding of nuclear factor B (NF-B), including the NF-B complex c-Rel/RelA, and activator protein 1 (AP-1, including N-terminal phosphorylated c-Jun) to the IL-8 promoter. Both crystals induced transcriptional activation of the IL-8 promoter, which was dependent on activation of c-Rel/RelA and AP-1. Activation of the NF-IL-6 transcription factor played a lesser role. Finally, crystal-induced IL-8 promoter activation was mediated by activation of the ERK-1/ERK-2 pathway, as demonstrated by transfection of dominant-negative raf-1. Conclusion. These results indicate that ERK-1/ ERK-2 signaling and transcriptional activation through AP-1 and NF-B are essential for the induction of IL-8 expression in mononuclear phagocytes in response to CPPD and MSU crystals.

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Phosphocitrate Inhibits a Basic Calcium Phosphate and Calcium Pyrophosphate Dihydrate Crystal-induced Mitogen-activated Protein Kinase Cascade Signal Transduction Pathway

Cited by 82 publications

References 29 publications

Basic calcium phosphate crystals activate c-fos expression through a Ras/ERK dependent signaling mechanism

Basic calcium phosphate crystals activate c-fos expression through a Ras/ERK dependent signaling mechanism

Basic calcium phosphate crystal induction of collagenase 1 and stromelysin expression is dependent on a p42/44 mitogen-activated protein kinase signal transduction pathway

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