Ras Guanine Nucleotide-releasing Protein-4 (RasGRP4) Involvement in Experimental Arthritis and Colitis

Adachi, Roberto; Krilis, Steven A.; Nigrović, Peter A.; Hamilton, Matthew J.; Chung, Kyungemee; Thakurdas, Shakeel M.; Boyce, Joshua A.; Anderson, Paul S.; Stevens, Richard L

doi:10.1074/jbc.m112.360388

Cited by 21 publications

(31 citation statements)

References 45 publications

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“…We showed that rats with CIA that had received an intraarticular injection of a RasGRP‐4–specific siRNA had significantly improved arthritis and scarce joint destruction, consistent with the recent finding that RasGRP‐4–null B6 mice are resistant to experimental K/BxN arthritis (). Thus, the importance of RasGRP‐4 in a second well‐established experimental arthritis model has now been shown.…”

Section: Discussionsupporting

confidence: 88%

“…The RasGRP‐4+ cells in mouse synovium that are essential in K/BxN arthritis induced by anti–glucose‐6‐phosphate isomerase autoantibodies have not yet been identified. Nevertheless, the finding that experimental arthritis could not be induced in RasGRP‐4–null B6 mice documented for the first time an essential role for this GEF in the effector phase of the IgG/C5a‐mediated murine arthritis model (). In support of these mouse data, we identified defective isoforms of RasGRP‐4 in the peripheral blood mononuclear cells of a subset of patients with RA ().…”

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confidence: 99%

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Ras Guanine Nucleotide–Releasing Protein 4 Is Aberrantly Expressed in the Fibroblast‐like Synoviocytes of Patients With Rheumatoid Arthritis and Controls Their Proliferation

Kono

Yasuda

Stevens

et al. 2015

Arthritis & Rheumatology

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Objective. Ras guanine nucleotide-releasing protein 4 (RasGRP-4) is a calcium-regulated guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor not normally expressed in fibroblasts. While RasGRP-4-null mice are resistant to arthritis induced by anti-glucose-6-phosphate isomerase autoantibodies, the relevance of these findings to humans is unknown. We undertook this study to evaluate the importance of RasGRP-4 in the pathogenesis of human and rat arthritis.Methods. Synovial tissue from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were evaluated immunohistochemically for the presence of RasGRP-4 protein. Fibroblast-like synoviocytes (FLS) were isolated from synovial samples, and expression of RasGRP-4 was evaluated by real-time quantitative reverse transcription-polymerase chain reaction analyses. The proliferation potency of FLS was evaluated by exposing the cells to a RasGRP-4-specific small interfering RNA (siRNA). Finally, the ability of RasGRP-4-specific siRNAs to hinder type II collagen-induced arthritis in rats was evaluated to confirm the importance of the signaling protein in the disease.Results. Unexpectedly, RasGRP-4 protein was detected in the synovial hyperplastic lining, where proliferating FLS preferentially reside. FLS isolated from tissues obtained from a subpopulation of RA patients expressed much more RasGRP-4 than did FLS from examined OA patients. Moreover, the level of RasGRP-4 transcript was correlated with the FLS proliferation rate. The ability of cultured FLS to divide was diminished when they were treated with RasGRP-4-specific siRNAs. The intraarticular injection of RasGRP-4-specific siRNAs also dampened experimental arthritis in rats.Conclusion. RasGRP-4 is aberrantly expressed in FLS and helps regulate their growth. This intracellular signaling protein is therefore a candidate target for dampening proliferative synovitis and joint destruction.

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Section: Discussionsupporting

confidence: 88%

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confidence: 99%

Ras Guanine Nucleotide–Releasing Protein 4 Is Aberrantly Expressed in the Fibroblast‐like Synoviocytes of Patients With Rheumatoid Arthritis and Controls Their Proliferation

Kono

Yasuda

Stevens

et al. 2015

Arthritis & Rheumatology

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“…Subsequently, two independent groups generated RasGRP4 deficient mice and examined its role in mast cells development and function. Both groups demonstrated that RasGRP4 is dispensable for mast cell development and maturation (Adachi et al, 2012; Zhu et al, 2012). The Zhang laboratory showed that RasGRP4 deficiency results in impaired FcεRI-dependent mast cell function such as degranulation and cytokines production.…”

Section: Rasgrp2 and Rasgrp4 In Non-oncogenic Settingsmentioning

confidence: 99%

“…The Stevens group investigated the consequences of RasGRP4 deficiency in two inflammation models, which involve mast cells. Interestingly, they show that RasGRP4 knockout mice are protected from DSS (dextran sodium sulfate)-induced acute colitis as well as from one type of experimental arthritis (Adachi et al, 2012). However, since both of these models also involve other cell types of innate and adaptive arms of the immune system, it is difficult to point out which cells are affected (and how?)…”

Section: Rasgrp2 and Rasgrp4 In Non-oncogenic Settingsmentioning

confidence: 99%

RasGRP Ras guanine nucleotide exchange factors in cancer

2013

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Summary RasGRP proteins are activators of Ras and other related small GTPases by the virtue of functioning as guanine nucleotide exchange factors (GEFs). In vertebrates, four RasGRP family members have been described. RasGRP-1 through −4 share many structural domains but there are also subtle differences between each of the different family members. Whereas SOS RasGEFs are ubiquitously expressed, RasGRP proteins are expressed in distinct patterns, such as in different cells of the hematopoietic system and in the brain. Most studies have concentrated on the role of RasGRP proteins in the development and function of immune cell types because of the predominant RasGRP expression profiles in these cells and the immune phenotypes of mice deficient for Rasgrp genes. However, more recent studies demonstrate that RasGRPs also play an important role in tumorigenesis. Examples are skin- and hematological-cancers but also solid malignancies such as melanoma or prostate cancer. These novel studies bring up many new and unanswered questions related to the molecular mechanism of RasGRP-driven oncogenesis, such as new receptor systems that RasGRP appears to respond to as well as regulatory mechanism for RasGRP expression that appear to be perturbed in these cancers. Here we will review some of the known aspects of RasGRP biology in lymphocytes and will discuss the exciting new notion that RasGRP Ras exchange factors play a role in oncogenesis downstream of various growth factor receptors.

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“…We then employed these mice in various models. To that end, RasGRP4 is a signaling protein expressed in MCs (20) that controls the release of cytokines and preformed mediators (21). Our inability to induce K/BxN arthritis in RasGRP4-null B6 mice (21) supports the conclusion made in earlier Kit W /Kit W-v mouse studies that synovial MCs release factors that have adverse roles in acute inflammatory arthritis.…”

Section: Introductionmentioning

confidence: 99%

Mast Cell–Restricted, Tetramer-Forming Tryptases Induce Aggrecanolysis in Articular Cartilage by Activating Matrix Metalloproteinase-3 and -13 Zymogens

Magarinos

Bryant

Fosang

et al. 2013

The Journal of Immunology

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Mouse mast cell protease (mMCP)-6-null C57BL/6 mice lost less aggrecan proteoglycan from the extracellular matrix of their articular cartilage during inflammatory arthritis than wild-type (WT) C57BL/6 mice, suggesting that this mast cell (MC)-specific mouse tryptase plays prominent roles in articular cartilage catabolism. We used ex vivo mouse femoral head explants to determine how mMCP-6 and its human ortholog hTryptase-β mediate aggrecanolysis. Exposure of the explants to recombinant hTryptase-β, recombinant mMCP-6, or lysates harvested from WT mouse peritoneal MCs (PMCs) significantly increased the levels of enzymatically active matrix metalloproteinases (MMP) in cartilage and significantly induced aggrecan loss into the conditioned media, relative to replicate explants exposed to medium alone or lysates collected from mMCP-6-null PMCs. Treatment of cartilage explants with tetramer-forming tryptases generated aggrecan fragments that contained C-terminal DIPEN and N-terminal FFGVG neoepitopes, consistent with MMP-dependent aggrecanolysis. In support of these data, hTryptase-β was unable to induce aggrecan release from the femoral head explants obtained from Chloe mice that resist MMP cleavage at the DIPEN↓FFGVG site in the interglobular domain of aggrecan. In addition, the abilities of mMCP-6-containing lysates from WT PMCs to induce aggrecanolysis were prevented by inhibitors of MMP-3 and MMP-13. Finally, recombinant hTryptase-β was able to activate latent pro-MMP-3 and pro-MMP-13 in vitro. The accumulated data suggest that human and mouse tetramer-forming tryptases are MMP convertases that mediate cartilage damage and the proteolytic loss of aggrecan proteoglycans in arthritis, in part, by activating the zymogen forms of MMP-3 and MMP-13 which are constitutively present in articular cartilage.

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Ras Guanine Nucleotide-releasing Protein-4 (RasGRP4) Involvement in Experimental Arthritis and Colitis

Cited by 21 publications

References 45 publications

Ras Guanine Nucleotide–Releasing Protein 4 Is Aberrantly Expressed in the Fibroblast‐like Synoviocytes of Patients With Rheumatoid Arthritis and Controls Their Proliferation

Ras Guanine Nucleotide–Releasing Protein 4 Is Aberrantly Expressed in the Fibroblast‐like Synoviocytes of Patients With Rheumatoid Arthritis and Controls Their Proliferation

RasGRP Ras guanine nucleotide exchange factors in cancer

Mast Cell–Restricted, Tetramer-Forming Tryptases Induce Aggrecanolysis in Articular Cartilage by Activating Matrix Metalloproteinase-3 and -13 Zymogens

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