Chaly Yury, Marinov Anthony D, Oxburgh Leif, Bushnell Daniel S, Hirsch Raphael
Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15224, USA.
Arthritis Rheum. 2012 Apr;64(4):1082-8. doi: 10.1002/art.33422. Epub 2011 Oct 17.
FSTL1 is a secreted glycoprotein that exacerbates murine arthritis and is overexpressed in human arthritis. The aim of this study was to determine the mechanism by which FSTL1 promotes arthritis.
Collagen-induced arthritis was induced in mice hypomorphic for FSTL1, generated with a gene trap-targeted mutant embryonic stem cell line. Arthritis was assessed by measuring paw swelling and using a qualitative arthritis index. Bone marrow-derived mesenchymal stromal cells from hypomorphic mice, as well as mouse stromal ST2 cells transduced with short hairpin RNA to suppress FSTL1 expression, were stimulated with interleukin-1β (IL-1β), tumor necrosis factor α, and IL-17. The monocyte cell line U937, which does not express FSTL1, was transfected with a plasmid encoding FSTL1 and stimulated with phorbol myristate acetate and lipopolysaccharide. Cell supernatants were assayed for IL-6, IL-8, monocyte chemotactic protein 1 (MCP-1), and FSTL1 by enzyme-linked immunosorbent assay.
FSTL1 hypomorphic mice had reduced levels of FSTL1 compared to littermate controls. Following induction of arthritis, a significant correlation was observed between serum FSTL1 levels and both paw swelling and the arthritis index. Similar correlations were observed between the amount of FSTL1 produced by mesenchymal stromal cells, stromal ST2 cells, and monocytes and the secretion of IL-6, IL-8, and MCP-1.
These findings demonstrate that FSTL1 up-regulates proinflammatory mediators important in the pathology of arthritis, and that serum levels of FSTL1 correlate with severity of arthritis. The latter supports the possibility that FSTL1 might be a target for treatment of certain forms of arthritis.
FSTL1是一种分泌型糖蛋白，可加剧小鼠关节炎，且在人类关节炎中过表达。本研究旨在确定FSTL1促进关节炎的机制。
利用基因陷阱靶向突变胚胎干细胞系构建FSTL1低表达小鼠，诱导其发生胶原诱导性关节炎。通过测量爪肿胀情况并使用定性关节炎指数评估关节炎。用白细胞介素-1β（IL-1β）、肿瘤坏死因子α和IL-17刺激FSTL1低表达小鼠的骨髓间充质基质细胞以及转导短发夹RNA以抑制FSTL1表达的小鼠基质ST2细胞。将不表达FSTL1的单核细胞系U937用编码FSTL1的质粒转染，并用佛波酯肉豆蔻酸酯和脂多糖刺激。通过酶联免疫吸附测定法检测细胞上清液中的IL-6、IL-8、单核细胞趋化蛋白1（MCP-1）和FSTL1。
与同窝对照相比，FSTL1低表达小鼠的FSTL1水平降低。诱导关节炎后，血清FSTL1水平与爪肿胀及关节炎指数之间存在显著相关性。在间充质基质细胞、基质ST2细胞和单核细胞产生的FSTL1量与IL-6、IL-8和MCP-1的分泌之间也观察到类似的相关性。
这些发现表明，FSTL1上调了在关节炎病理过程中重要的促炎介质，且FSTL1的血清水平与关节炎严重程度相关。后者支持FSTL1可能是某些形式关节炎治疗靶点的可能性。
