CD248 and its cytoplasmic domain: A therapeutic target for arthritis

Maia, Margarida; Vriese, Astrid De; Janssens, Tom; Moons, Michaël; Landuyt, Kristel Van; Tavernier, Jan; Lories, Rik; Conway, Edward M.

doi:10.1002/art.27701

Cited by 66 publications

(97 citation statements)

References 48 publications

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“…However, expression is downregulated postnatally but upregulated during tissue remodeling. We found CD248-expressing fibroblasts predominantly in the sub-lining tissue of the inflammatory synovium, consistent with previous studies [32]. As expected from their anatomical location, CD248 + SF did not invade the implants of cartilage in vivo.…”

Section: Discussionsupporting

confidence: 92%

Rheumatoid synovial fibroblasts differentiate into distinct subsets in the presence of cytokines and cartilage

et al. 2016

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BackgroundWe investigated two distinct synovial fibroblast populations that were located preferentially in the lining or sub-lining layers and defined by their expression of either podoplanin (PDPN) or CD248, and explored their ability to undergo self-assembly and transmigration in vivo.MethodsSynovial fibroblasts (SF) were cultured in vitro and phenotypic changes following stimulation with interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1 were examined. To examine the phenotype of SF in vivo, a severe combined immunodeficiency (SCID) human-mouse model of cartilage destruction was utilised.ResultsSF in the lining layer in rheumatoid arthritis (RA) expressed high levels of PDPN compared to the normal synovium, whereas CD248 expression was restricted to sub-lining layer cells. TNF-α or IL1 stimulation in vitro resulted in an increased expression of PDPN. In contrast, stimulation with TGF-β1 induced CD248 expression. In the SCID human-mouse model, rheumatoid SF recapitulated the expression of PDPN and CD248. Fibroblasts adjacent to cartilage expressed PDPN, and attached to, invaded, and degraded cartilage. PDPN+ CD248– SF preceded the appearance of PDPN– CD248+ cells in contralateral implants.ConclusionsWe have identified two distinct SF populations identified by expression of either PDPN or CD248 which are located within different anatomical compartments of the inflamed synovial membrane. These markers discriminate between SF subsets with distinct biological properties. As PDPN-expressing cells are associated with early fibroblast migration and cartilage erosion in vivo, we propose that PDPN-expressing cells may be an attractive therapeutic target in RA.

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Section: Discussionsupporting

confidence: 92%

Rheumatoid synovial fibroblasts differentiate into distinct subsets in the presence of cytokines and cartilage

et al. 2016

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Section: Discussionmentioning

confidence: 99%

“…42 In addition, it has been demonstrated recently that embryonic fibroblasts expressing endosialin with a truncated cytoplasmic domain are impaired in their ability to bind U937 monocytes. 43 Therefore, endosialin may also modulate selective vessel pruning via its ability to promote localized leukocyte recruitment.Very little is known about the mechanisms by which particular vessels are selected for pruning while adjacent vessels remain patent. Our data presented herein demonstrate that endosialin plays a role in this process and further suggest that the activity of endosialin could be restricted to selected vessels by the regulated availability of its ligand.…”

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confidence: 99%

Pericytes promote selective vessel regression to regulate vascular patterning

Simonavicius

Ashenden

Weverwijk

et al. 2012

Blood

105

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Blood vessel networks form in a 2-step process of sprouting angiogenesis followed by selective branch regression and stabilization of remaining vessels. Pericytes are known to function in stabilizing blood vessels, but their role in vascular sprouting and selective vessel regression is poorly understood. The endosialin (CD248) receptor is expressed by pericytes associated with newly forming but not stable quiescent vessels. In the present study, we used the Endosialin ؊/؊ mouse as a means to uncover novel roles for pericytes during the process of vascular network formation. We demonstrate in a postnatal retina model that Endosialin ؊/؊ mice have normal vascular sprouting but are defective in selective vessel regression, leading to increased vessel density. Examination of the Endosialin ؊/؊ mouse tumor vasculature revealed an equivalent phenotype, indicating that pericytes perform a hitherto unidentified function to promote vessel destabilization and regression in vivo in both physiologic and pathologic angiogenesis. Mechanistically, Endosialin ؊/؊ mice have no defect in pericyte recruitment. Rather, endosialin binding to an endothelial associated, but not a pericyte associated, basement membrane component induces endothelial cell apoptosis and detachment. The results of the present study advance our understanding of pericyte biology and pericyte/endothelial cell cooperation during vascular patterning and have implications for the design of both proand antiangiogenic therapies. (Blood. 2012;120(7):1516-1527) IntroductionThe expansion of existing blood vessels, known as angiogenesis, is a critical process that occurs in response to an insufficient supply of nutrients and oxygen during development and tissue regeneration. The deregulated generation and abnormal remodeling of blood vessels can promote the expansion of tumors or fail to restore tissue oxygenation adequately, contributing to ischemic disease progression (eg, in diabetic retinopathy). Therefore, the identification of the cellular and molecular targets for therapeutic strategies to influence vascular network formation and remodeling is of considerable clinical importance. 1,2 Angiogenesis is initiated in response to local production of proangiogenic factors, in particular VEGF-A, which promote new vascular sprout formation by the induction and migration of leading tip cells and by stimulating the proliferation of neighboring stalk cells. In addition, VEGFmediated regulation of the Delta-like 4/Notch1 signaling pathway ensures the correct spatiotemporal coordination of tip versus stalk cell specialization required for organized patterning of new vascular networks. 3 Subsequent to sprouting angiogenesis, the initial vascular plexus is remodeled extensively. Key to this remodeling is the pruning of unwanted capillaries through selective branch regression. The remaining vessels mature and are stabilized, which marks the end of vessel plasticity and reflects the quiescent state of the new hierarchical vascular network. With the exception of the complete regr...

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“…Indeed, using anti-IL-6 and anti-IL-1 receptor mABs, Kawane et al (28) were able to impede the "cytokine storm" and block joint swelling. Furthermore, Maia et al (29) used ArthroMAB to induce CAIA, and found that removing the cytoplasmic domain of CD248 impaired TNF-α-induced monocyte adhesion, underscoring the importance of regulating TNF-α production in rheumatoid arthritis. Recent clinical trials demonstrated that soluble tumor necrosis factor-receptor immunoglobulin fusion protein (TNFRIg) and anti-TNF-α antibodies can reduce synovitis and serum markers for inflammation.…”

Section: Discussionmentioning

confidence: 99%

Whole-body deletion of LPS-induced TNF-α factor (LITAF) markedly improves experimental endotoxic shock and inflammatory arthritis

Merrill

You

Constable

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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LPS-induced TNF-α factor (LITAF) mediates cytokine expression in response to endotoxin challenge. Previously, we reported that macrophage-specific LITAF-deficient (macLITAF −/− ) mice exposed to LPS have a delayed onset in the serum levels of proinflammatory cytokines and prolonged persistence of anti-inflammatory cytokines, but only partial protection from endotoxic shock. We postulated that greater protection might be achieved if LITAF were deleted from all LITAF-producing cells, including macrophages. Using a Cre-loxP system, we engineered a tamoxifen-induced recombination mouse [tamLITAF(i)] that resulted in whole-body LITAF deficiency. Our findings demonstrate that (i) tamLITAF(i) −/− mice are more resistant to systemic Escherichia coli LPS-induced lethality than our previous macLITAF −/− mice, providing evidence that LITAF-producing cells other than LysMCre-positive cells play an important role in mediating endotoxic shock; (ii) tamLITAF(i) −/− mice show a similar pattern of cytokine expression with decreased proinflammatory and prolonged anti-inflammatory mediators compared with WT mice; and (iii) tamLITAF(i) −/− mice, compared with WT mice, display a significant reduction in bone resorption and inflammation associated with a local chronic inflammatory disease-namely, collagen antibody-induced arthritis. Our findings offer a unique model to study the role of LITAF in systemic and chronic local inflammatory processes, and pave the way for anti-LITAF therapeutic approaches for the treatment of TNF-mediated inflammatory diseases.septic shock | multiplex

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CD248 and its cytoplasmic domain: A therapeutic target for arthritis

Cited by 66 publications

References 48 publications

Rheumatoid synovial fibroblasts differentiate into distinct subsets in the presence of cytokines and cartilage

Rheumatoid synovial fibroblasts differentiate into distinct subsets in the presence of cytokines and cartilage

Pericytes promote selective vessel regression to regulate vascular patterning

Whole-body deletion of LPS-induced TNF-α factor (LITAF) markedly improves experimental endotoxic shock and inflammatory arthritis

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