Sato Tomoo, Fujii Ryoji, Konomi Koji, Yagishita Naoko, Aratani Satoko, Araya Natsumi, Aono Hiroyuki, Yudoh Kazuo, Suzuki Noboru, Beppu Moroe, Yamano Yoshihisa, Nishioka Kusuki, Nakajima Toshihiro
St. Marianna University School of Medicine, Kawasaki, Japan.
Arthritis Rheum. 2011 Dec;63(12):3833-42. doi: 10.1002/art.30617.
To identify novel genes associated with dysregulated proliferation of activated synovial fibroblasts, which are involved in arthritic joint destruction.
We performed transcriptome analysis to identify genes that were up-regulated in the foot joints of mice with collagen-induced arthritis (CIA). The effect of candidate genes on proliferation of synovial fibroblasts was screened using antisense oligodeoxynucleotides and small interfering RNAs (siRNAs). We characterized the expression and function of a novel gene, synoviocyte proliferation-associated in collagen-induced arthritis 1 (SPACIA1)/serum amyloid A-like 1 (SAAL1) using antibodies and siRNA and established transgenic mice to examine the effect of SPACIA1/SAAL1 overexpression in CIA.
Human and mouse SPACIA1/SAAL1 encoded 474 amino acid proteins that shared 80% homology. SPACIA1/SAAL1 was primarily expressed in the nucleus of rheumatoid arthritis (RA) synovial fibroblasts and was highly expressed in the hyperplastic lining of inflamed synovium. In addition, its expression level in RA- or osteoarthritis (OA)-affected synovial tissue was positively correlated with the thickness of the synovial lining. Furthermore, SPACIA1/SAAL1 siRNA inhibited the proliferation of synovial fibroblasts, especially tumor necrosis factor α-induced synovial fibroblasts, by blocking entry into the S phase without inducing apoptosis. Finally, transgenic mice overexpressing SPACIA1/SAAL1 exhibited early onset and rapid progression of CIA.
These results suggest that SPACIA1/SAAL1 is necessary for abnormal proliferation of synovial fibroblasts and its overexpression is associated with the progression of synovitis in mice and humans. Thus, therapy targeting SPACIA1/SAAL1 might have potential as an inhibitor of synovial proliferation in RA and/or OA.
鉴定与活化滑膜成纤维细胞增殖失调相关的新基因，这些细胞参与关节炎性关节破坏。
我们进行了转录组分析，以鉴定在胶原诱导性关节炎（CIA）小鼠足关节中上调的基因。使用反义寡脱氧核苷酸和小干扰RNA（siRNA）筛选候选基因对滑膜成纤维细胞增殖的影响。我们使用抗体和siRNA对一种新基因——胶原诱导性关节炎1中滑膜细胞增殖相关蛋白（SPACIA1）/血清淀粉样蛋白A样蛋白1（SAAL1）的表达和功能进行了表征，并建立了转基因小鼠来研究SPACIA1/SAAL1过表达在CIA中的作用。
人和小鼠的SPACIA1/SAAL1编码474个氨基酸的蛋白质，它们具有80%的同源性。SPACIA1/SAAL1主要在类风湿关节炎（RA）滑膜成纤维细胞的细胞核中表达，在炎症滑膜的增生衬里中高表达。此外，其在RA或骨关节炎（OA）受累滑膜组织中的表达水平与滑膜衬里的厚度呈正相关。此外，SPACIA1/SAAL1 siRNA通过阻止进入S期而不诱导凋亡来抑制滑膜成纤维细胞的增殖，尤其是肿瘤坏死因子α诱导的滑膜成纤维细胞。最后，过表达SPACIA1/SAAL1的转基因小鼠表现出CIA的早期发病和快速进展。
这些结果表明，SPACIA1/SAAL1是滑膜成纤维细胞异常增殖所必需的，其过表达与小鼠和人类滑膜炎的进展相关。因此，靶向SPACIA1/SAAL1的治疗可能具有作为RA和/或OA滑膜增殖抑制剂的潜力。
