The Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York 14642, USA.
Adv Exp Med Biol. 2010;658:1-10. doi: 10.1007/978-1-4419-1050-9_1.
A common feature of autoimmune diseases is the perpetual production of macrophage, dendritic and/or osteoclast effector cells, which mediate parenchymal tissue destruction in end organs. In support of this, we have demonstrated previously that patients and mice with inflammatory-erosive arthritis have a marked increase in circulating CD11b+ precursor cells, which are primed for osteoclastogenesis, and that this increase in osteoclast precursors (OCPs) is due to systemically increased TNF production. From these data, we proposed a unifying hypothesis to explain these osteoimmunologic findings during the pathogenesis of inflammatory-erosive arthritis, which has three postulates: (1) myelopoiesis chronically induced by TNF has profound effects on the bone marrow and joint tissues that should be evident from a longitudinal MRI; (2) TNF alters the chemokine/chemokine receptor axis in the bone marrow to stimulate OCP release into the blood, and (3) OCP-mediated lymphangiogenesis occurs in the end organ as a compensatory mechanism to drain the inflammation and remove by-products of joint catabolism. Here, we describe our recent experimental findings that support these hypotheses and speculate on how this information can be used as diagnostic biomarkers and tools to discover novel therapies to treat patients with inflammatory-erosive arthritis.
自身免疫性疾病的一个共同特征是持续产生巨噬细胞、树突状细胞和/或破骨细胞效应细胞，这些细胞介导实质组织在终末器官中的破坏。为此，我们之前已经证明，患有炎症性侵蚀性关节炎的患者和小鼠循环中 CD11b+前体细胞明显增加，这些前体细胞已经为破骨细胞生成做好了准备，而破骨细胞前体（OCP）的增加是由于 TNF 全身性增加所致。根据这些数据，我们提出了一个统一的假说来解释炎症性侵蚀性关节炎发病过程中的这些骨免疫学发现，该假说有三个假设：（1）TNF 慢性诱导的骨髓细胞生成对骨髓和关节组织有深远的影响，这应该从纵向 MRI 中明显看出；（2）TNF 改变骨髓中的趋化因子/趋化因子受体轴，刺激 OCP 释放到血液中，（3）OCP 介导的淋巴管生成发生在终末器官中，作为一种代偿机制，以排出炎症并清除关节分解代谢的副产物。在这里，我们描述了我们最近的实验发现，这些发现支持这些假设，并推测如何将这些信息用作诊断生物标志物和工具，以发现治疗炎症性侵蚀性关节炎患者的新疗法。
