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Salubrinal acts as a Dusp2 inhibitor and suppresses inflammation in anti-collagen antibody-induced arthritis.

ABSTRACT: Dual-specificity phosphatase 2 (Dusp2; also called phosphatase of activated cells 1, PAC1) is highly expressed in activated immune cells. We examined whether a potential inhibitor of Dusp2, salubrinal, prevents inflammatory cytokine expression in immune cells and arthritic responses in a mouse model of anti-collagen antibody-induced arthritis (CAIA). Salubrinal is a synthetic chemical that inhibits de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2?). In this study, we examined the effects of salubrinal on expression of inflammation linked genes as well as a family of DUSP genes using genome-wide microarrays, qPCR, and RNA interference. We also evaluated the effects of salubrinal on arthritic responses in CAIA mice using clinical and histological scores. The results revealed that salubrinal decreased inflammatory gene expression in macrophages, T lymphocytes, and mast cells. Dusp2 was suppressed by salubrinal in LPS-activated macrophages as well as PMA/ionomycin-activated T lymphocytes and mast cells. Furthermore, a partial silencing of Dusp2 downregulated IL1? and Cox2, and the inflammatory signs of CAIA mice were significantly suppressed by salubrinal. Collectively, this study presents a novel therapeutic possibility of salubrinal for inflammatory arthritis such as RA through inhibition of Dusp2.

SUBMITTER: Hamamura K

PROVIDER: S-EPMC4339503 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Salubrinal acts as a Dusp2 inhibitor and suppresses inflammation in anti-collagen antibody-induced arthritis.

Hamamura Kazunori K Nishimura Akinobu A Chen Andy A Takigawa Shinya S Sudo Akihiro A Yokota Hiroki H

Cellular signalling 20150122 4

Dual-specificity phosphatase 2 (Dusp2; also called phosphatase of activated cells 1, PAC1) is highly expressed in activated immune cells. We examined whether a potential inhibitor of Dusp2, salubrinal, prevents inflammatory cytokine expression in immune cells and arthritic responses in a mouse model of anti-collagen antibody-induced arthritis (CAIA). Salubrinal is a synthetic chemical that inhibits de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). In this study, we ...[more]

PMID: 25619567

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Project description:Collagen triple helix repeat-containing1 (Cthrc1) has previously been implicated in osteogenic differentiation and positive regulation of bone mass, however, the underlying mechanisms remain unclear. Here we characterized the bone phenotype of a novel Cthrc1 null mouse strain using bone histomorphometry, ?CT analysis and functional readouts for bone strength. In male Cthrc1 null mice both trabecular bone as well as cortical bone formation was impaired, whereas in female Cthrc1 null mice only trabecular bone parameters were altered. Novel and highly specific monoclonal antibodies revealed that CTHRC1 is expressed by osteocytes and osteoblasts, but not osteoclasts. Furthermore, Cthrc1 null mice exhibited increased bone resorption with increased number of osteoclast and increased osteoclast activity together with enhanced expression of osteoclastogenic genes such as c-Fos, Rankl, Trap, and Nfatc1. Differentiation of bone marrow-derived monocytes isolated from Cthrc1 null mice differentiated into osteoclasts as effectively as those from wildtype mice. In the presence of CTHRC1 osteoclastogenic differentiation of bone marrow-derived monocytes was dramatically inhibited as was functional bone resorption by osteoclasts. This process was accompanied by downregulation of osteoclastogenic marker genes, indicating that extrinsically derived CTHRC1 is required for such activity. In vitro, CTHRC1 had no effect on osteogenic differentiation of bone marrow stromal cells, however, calvarial osteoblasts from Cthrc1 null mice exhibited reduced osteogenic differentiation compared to osteoblasts from wildtypes. In a collagen antibody-induced arthritis model Cthrc1 null mice suffered significantly more severe inflammation and joint destruction than wildtypes, suggesting that CTHRC1 expressed by the activated synoviocytes has anti-inflammatory effects. Mechanistically, we found that CTHRC1 inhibited NF?B activation by preventing I?B? degradation while also inhibiting ERK1/2 activation. Collectively our studies demonstrate that CTHRC1 secreted from osteocytes and osteoblasts functions as an inhibitor of osteoclast differentiation via inhibition of NF?B-dependent signaling. Furthermore, our data suggest that CTHRC1 has potent anti-inflammatory properties that limit arthritic joint destruction.

Dataset Information

Salubrinal acts as a Dusp2 inhibitor and suppresses inflammation in anti-collagen antibody-induced arthritis.

Publications

Salubrinal acts as a Dusp2 inhibitor and suppresses inflammation in anti-collagen antibody-induced arthritis.

Similar Datasets

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