Lories Rik J U, Derese Inge, de Bari Cosimo, Luyten Frank P
Katholieke Universiteit, Leuven, Belgium.
Arthritis Rheum. 2007 Feb;56(2):489-97. doi: 10.1002/art.22372.
To study the relationship between inflammation and remodeling by inhibiting tumor necrosis factor alpha (TNFalpha) in male DBA/1 mice with spontaneous arthritis, a model of spondylarthritis (SpA).
TNFalpha was inhibited using etanercept, a soluble TNF receptor. The efficacy of the dose used (25 micro g/mouse) was confirmed in methylated bovine serum albumin (mBSA)-induced monarthritis, a model of inflammation-driven joint destruction. Male DBA/1 mice with spontaneous arthritis were caged together from the age of 10 weeks onward and were treated twice weekly with etanercept. The incidence and clinical severity of disease were recorded. Mice were killed at age 25 weeks, and histomorphologic analysis was performed. The presence of TNFalpha, NF-kappaB, and Smad signaling was studied using immunohistochemistry. Entheseal endochondral bone formation was modeled using micromass cultures of periosteal cells.
Etanercept inhibited mouse TNFalpha in vitro and in vivo. Etanercept treatment of mBSA-induced arthritis had a significant effect on the severity of disease. Etanercept did not affect the incidence or severity of spontaneous arthritis. Pathologic analysis revealed no differences between etanercept-treated and phosphate buffered saline-treated mice. TNFalpha-positive cells were observed in the synovium, in vessel-associated cells, in fibrocartilage, and in new cartilage. Activation of Smad signaling was observed in earlier stages of disease than was active NF-kappaB signaling. TNFalpha inhibited chondrogenesis in the micromass model.
Inhibition of TNF did not affect the severity and incidence of joint ankylosis in a mouse model of SpA. Therefore, the process of entheseal ankylosis may be independent of TNF. New tissue formation in SpA could be considered an additional and specific therapeutic target.
通过抑制肿瘤坏死因子α（TNFα），研究男性DBA/1自发关节炎小鼠（一种脊柱关节炎（SpA）模型）中炎症与重塑之间的关系。
使用可溶性TNF受体依那西普抑制TNFα。在甲基化牛血清白蛋白（mBSA）诱导的单关节炎（一种炎症驱动的关节破坏模型）中证实了所用剂量（25μg/小鼠）的疗效。10周龄起将患有自发关节炎的雄性DBA/1小鼠关在一起，每周用依那西普治疗两次。记录疾病的发病率和临床严重程度。在25周龄时处死小鼠并进行组织形态学分析。使用免疫组织化学研究TNFα、NF-κB和Smad信号通路的存在情况。使用骨膜细胞的微团培养对附着点软骨内骨形成进行建模。
依那西普在体外和体内均能抑制小鼠TNFα。依那西普治疗mBSA诱导的关节炎对疾病严重程度有显著影响。依那西普不影响自发关节炎的发病率或严重程度。病理分析显示依那西普治疗组和磷酸盐缓冲盐水治疗组小鼠之间无差异。在滑膜、血管相关细胞、纤维软骨和新软骨中观察到TNFα阳性细胞。与活跃的NF-κB信号相比，在疾病早期观察到Smad信号的激活。TNFα在微团模型中抑制软骨形成。
在SpA小鼠模型中，抑制TNF不影响关节强直的严重程度和发病率。因此，附着点强直的过程可能独立于TNF。SpA中的新组织形成可被视为一个额外的特异性治疗靶点。
