Evidence for uncoupling of inflammation and joint remodeling in a mouse model of spondylarthritis
Evidence for uncoupling of inflammation and joint remodeling in a mouse model of spondylarthritis
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DOI：
10.1002/art.22372
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发表时间：
2007-02-01
影响因子：
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通讯作者：
Luyten, Frank P.
中科院分区：
文献类型：
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作者：
Lories, Rik J. U.;Derese, Inge;Luyten, Frank P.
Objective.通过抑制肿瘤坏死因子α（TNF α），研究自发性关节炎（SpA）雄性DBA/1小鼠模型中炎症与重塑的关系。使用依那西普（一种可溶性TNF受体）抑制TNF α。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（25 μ g/小鼠）的疗效。从10周龄开始，将患有自发性关节炎的雄性DBA/1小鼠关在一起，每周两次用依那西普治疗。记录疾病的发生率和临床严重程度。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TNF α、NF-κ B和Smad信号传导的存在。利用骨膜细胞的微团培养建立附着点软骨内骨形成的模型。依那西普在体外和体内抑制小鼠TNF α。依那西普治疗mBSA诱导的关节炎对疾病的严重程度有显著影响。依那西普不影响自发性关节炎的发生率或严重程度。病理学分析显示依那西普处理的小鼠和磷酸盐缓冲盐水处理的小鼠之间没有差异。在滑膜、血管相关细胞、纤维软骨和新软骨中观察到TNF α阳性细胞。在疾病的早期阶段观察到Smad信号传导的激活，而不是活性NF-κ B信号传导。TNF α抑制微团模型中的软骨形成。在SpA小鼠模型中，抑制TNF并不影响关节强直的严重程度和发生率。因此，附着点强直的过程可能与TNF无关。SpA中的新组织形成可以被认为是额外的和特异性的治疗靶点。
Objective. To study the relationship between inflammation and remodeling by inhibiting tumor necrosis factor alpha (TNF alpha) in male DBA/1 mice with spontaneous arthritis, a model of spondylarthritis (SpA).Methods. TNF alpha was inhibited using etanercept, a soluble TNF receptor. The efficacy of the dose used (25 mu 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 TNF alpha, NF-kappa B, and Smad signaling was studied using immunohistochemistry. Entheseal endochondral bone formation was modeled using micromass cultures of periosteal cells.Results. Etanercept inhibited mouse TNF alpha 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. TNF alpha-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-kappa B signaling. TNF alpha inhibited chondrogenesis in the micromass model.Conclusion. 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.