Maia Margarida, de Vriese Astrid, Janssens Tom, Moons Michaël, van Landuyt Kristel, Tavernier Jan, Lories Rik J, Conway Edward M
Katholieke Universiteit-Leuven, Flanders Interuniversity Institute for Biotechnology (VIB)-Leuven, VIB-Ghent, and Ghent University, Ghent, Belgium.
Arthritis Rheum. 2010 Dec;62(12):3595-606. doi: 10.1002/art.27701.
CD248 is a transmembrane glycoprotein expressed on the surface of activated perivascular and fibroblast-like cells. This study was undertaken to explore the function of CD248 and its cytoplasmic domain in arthritis.
Synovial tissue biopsy samples from healthy controls, from patients with psoriatic arthritis (PsA), and from patients with rheumatoid arthritis (RA) were stained for CD248. Transgenic mice that were CD248-deficient (CD248-knockout [CD248(KO/KO) ]) or mice with CD248 lacking the cytoplasmic domain (CD248(CyD/CyD) ) were generated. Collagen antibody-induced arthritis (CAIA) was induced in these mice and in corresponding wild-type (WT) mice as controls. Clinical signs and histologic features of arthritis were evaluated. Cytokine levels were determined by enzyme-linked immunosorbent assay, and the number of infiltrating inflammatory cells was quantified by immunohistochemistry. In vitro studies were performed with fibroblasts from CD248-transgenic mouse embryos to explain the observed effects on inflammation.
Immunostaining of synovium from patients with PsA and patients with RA and that from mice after the induction of CAIA revealed strong CD248 expression in perivascular and fibroblast-like stromal cells. CD248(KO/KO) and CD248(CyD/CyD) mice had less severe arthritis, with lower plasma levels of proinflammatory cytokines, as compared with WT controls. Moreover, the joints of these mice had less synovial hyperplasia, reduced accumulation of inflammatory cells, and less articular cartilage and bone damage. Tumor necrosis factor α-induced monocyte adhesion to CD248(CyD/CyD) fibroblasts was impaired. CD248(CyD/CyD) fibroblasts exhibited reduced expression of hypoxia-inducible factor 1α, placental growth factor, vascular endothelial growth factor, and matrix metalloproteinase 9 activity in response to transforming growth factor β.
CD248 contributes to synovial hyperplasia and leukocyte accumulation in inflammatory arthritis, the effects of which are mediated partly via its cytoplasmic domain. CD248 is therefore a potential new target in the treatment of arthritis.
CD248是一种跨膜糖蛋白，表达于活化的血管周围细胞和成纤维细胞样细胞表面。本研究旨在探讨CD248及其胞质结构域在关节炎中的作用。
对健康对照者、银屑病关节炎（PsA）患者和类风湿关节炎（RA）患者的滑膜组织活检样本进行CD248染色。构建CD248基因缺陷型（CD248基因敲除[CD248(KO/KO)]）转基因小鼠以及缺失胞质结构域的CD248小鼠（CD248(CyD/CyD)）。在这些小鼠以及相应的野生型（WT）对照小鼠中诱导胶原抗体诱导的关节炎（CAIA）。评估关节炎的临床症状和组织学特征。通过酶联免疫吸附测定法测定细胞因子水平，通过免疫组织化学法定量浸润的炎性细胞数量。利用CD248转基因小鼠胚胎的成纤维细胞进行体外研究，以解释观察到的对炎症的影响。
PsA患者和RA患者的滑膜以及CAIA诱导后小鼠的滑膜免疫染色显示，血管周围细胞和成纤维细胞样基质细胞中CD248表达强烈。与WT对照相比，CD248(KO/KO)和CD248(CyD/CyD)小鼠的关节炎症状较轻，促炎细胞因子的血浆水平较低。此外，这些小鼠的关节滑膜增生较少，炎性细胞积聚减少，关节软骨和骨损伤也较少。肿瘤坏死因子α诱导的单核细胞与CD248(CyD/CyD)成纤维细胞的黏附受损。CD248(CyD/CyD)成纤维细胞在转化生长因子β刺激下，缺氧诱导因子1α、胎盘生长因子、血管内皮生长因子的表达降低，基质金属蛋白酶9活性降低。
CD248在炎性关节炎中促进滑膜增生和白细胞积聚，其作用部分通过其胞质结构域介导。因此，CD248是关节炎治疗中一个潜在的新靶点。
