Lories Rik J U, Daans Melina, Derese Inge, Matthys Patrick, Kasran Ahmad, Tylzanowski Przemko, Ceuppens Jan L, Luyten Frank P
University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium.
Arthritis Rheum. 2006 Jun;54(6):1736-46. doi: 10.1002/art.21897.
The balance between destruction and homeostatic or reparative responses determines the outcome of arthritis. Increasing evidence suggests a role for signaling pathways, essential for development and growth, in the maintenance of tissue homeostasis and attempts at repair. Inappropriate activation of such pathways may also have a role in disease progression. We undertook this study to determine the effect of shifting the balance in bone morphogenetic protein (BMP) signaling in different mouse models of arthritis.
Endogenous levels of noggin, a BMP antagonist, were reduced using heterozygous noggin(+/LacZ) mice in a model of inflammation-driven destruction (methylated bovine serum albumin [mBSA]-induced monarthritis), a model of systemic autoimmune arthritis (collagen-induced arthritis [CIA]), and a model of joint ankylosis (spontaneous arthritis in DBA/1 mice). In addition, we studied BMP inactivation by adenoviral noggin overexpression in destructive arthritis. Cartilage damage and activation of BMP signaling were studied by digital image analysis using Safranin O sulfated glycosaminoglycan staining and immunohistochemistry for phosphorylated Smads (Smads 1, 5, and 8), respectively.
Noggin haploinsufficiency provided protection for articular cartilage against destruction in mBSA-induced arthritis. Antagonist overexpression rendered cartilage more vulnerable in this model. Noggin gene transfer in knees affected by CIA also enhanced cartilage damage. Haploinsufficiency did not affect CIA, but noggin(+/LacZ) mice had an increased number of CD4-positive cells with normal immune responses. In noggin(+/LacZ) DBA/1 mice with spontaneous arthritis, we observed delayed progression from cartilage to bone formation.
Tight spatiotemporal control of BMP signaling appears to be critical in the response of joint tissues in models of arthritis.
破坏与稳态或修复反应之间的平衡决定了关节炎的结局。越来越多的证据表明，对发育和生长至关重要的信号通路在维持组织稳态及修复尝试中发挥作用。此类通路的不适当激活可能也在疾病进展中起作用。我们开展这项研究以确定在不同的关节炎小鼠模型中改变骨形态发生蛋白（BMP）信号平衡的影响。
在炎症驱动破坏模型（甲基化牛血清白蛋白[mBSA]诱导的单关节炎）、系统性自身免疫性关节炎模型（胶原诱导的关节炎[CIA]）和关节强直模型（DBA/1小鼠的自发性关节炎）中，使用杂合的头蛋白（noggin）（+/LacZ）小鼠降低内源性头蛋白水平，其为一种BMP拮抗剂。此外，我们通过在破坏性关节炎中腺病毒介导的头蛋白过表达研究BMP失活。分别使用番红O硫酸化糖胺聚糖染色和磷酸化Smads（Smads 1、5和8）免疫组织化学，通过数字图像分析研究软骨损伤和BMP信号激活。
在mBSA诱导的关节炎中，头蛋白单倍体不足为关节软骨提供了抗破坏保护。在该模型中拮抗剂过表达使软骨更易受损。在受CIA影响的膝关节中进行头蛋白基因转移也加剧了软骨损伤。单倍体不足不影响CIA，但头蛋白（+/LacZ）小鼠中具有正常免疫反应的CD4阳性细胞数量增加。在患有自发性关节炎的头蛋白（+/LacZ）DBA/1小鼠中，我们观察到从软骨到骨形成的进展延迟。
在关节炎模型中，BMP信号的严格时空控制对于关节组织的反应似乎至关重要。
