TSG-6 regulates bone remodeling through inhibition of osteoblastogenesis and osteoclast activation
TSG-6 regulates bone remodeling through inhibition of osteoblastogenesis and osteoclast activation
复制标题
DOI：
10.1074/jbc.m802138200
复制
发表时间：
2008-09-19
影响因子：
4.8
通讯作者：
Sabokbar, Afsaneh
中科院分区：
文献类型：
--
作者：
Mahoney, David J.;Mikecz, Katalin;Sabokbar, Afsaneh
TSG-6 是一种炎症诱导蛋白，在病理部位（包括关节炎关节）产生。在关节炎动物模型中，TSG-6 可防止关节损伤；这归因于其对中性粒细胞迁移和纤溶酶活性的抑制作用。在这里，我们研究了 TSG-6 是否可以直接影响骨侵蚀。我们的数据显示，TSG-6 抑制 RANKL 诱导的人和小鼠前体细胞的破骨细胞分化/活化，其中来自 TSG-6(-/)-小鼠的破骨细胞导致的牙本质侵蚀增加与这些动物中观察到的非常严重的关节炎一致。然而，未受到攻击的 TSG-6(-/)-小鼠的长骨被发现比对照组具有更高的小梁质量，这表明在没有炎症的情况下，TSG-6 在骨稳态中发挥作用；我们在未受攻击的野生型小鼠的骨髓中检测到 TSG-6 蛋白的表达。此外，我们观察到 TSG-6 可以抑制骨形态发生蛋白 2 (BMP-2) 介导的成骨细胞分化。相互作用分析表明，TSG-6 通过涉及其 Link 和 CUB 模块的复合表面直接与 RANKL 和 BMP-2（以及其他成骨 BMP，但不包括 BMP-3）结合。与此一致的是，全长蛋白是最大程度地抑制成骨细胞分化和破骨细胞激活所必需的，尽管分离的 Link 模块在后一种情况下保留了显着的活性。我们假设 TSG-6 在骨重塑中具有双重作用；一种是保护性的，它可以抑制关节炎等炎症性疾病中 RANKL 诱导的骨侵蚀；另一种是稳态的，它与 BMP-2 和 RANKL 的相互作用有助于平衡成骨细胞的矿化和破骨细胞的骨吸收。
TSG-6 is an inflammation-induced protein that is produced at pathological sites, including arthritic joints. In animal models of arthritis, TSG-6 protects against joint damage; this has been attributed to its inhibitory effects on neutrophil migration and plasmin activity. Here we investigated whether TSG-6 can directly influence bone erosion. Our data reveal that TSG-6 inhibits RANKL-induced osteoclast differentiation/activation from human and murine precursor cells, where elevated dentine erosion by osteoclasts derived from TSG-6(-/)-mice is consistent with the very severe arthritis seen in these animals. However, the long bones from unchallenged TSG-6(-/)-mice were found to have higher trabecular mass than controls, suggesting that in the absence of inflammation TSG-6 has a role in bone homeostasis; we have detected expression of the TSG-6 protein in the bone marrow of unchallenged wild type mice. Furthermore, we have observed that TSG-6 can inhibit bone morphogenetic protein-2 (BMP-2)-mediated osteoblast differentiation. Interaction analysis revealed that TSG-6 binds directly to RANKL and to BMP-2 (as well as other osteogenic BMPs but not BMP-3) via composite surfaces involving its Link and CUB modules. Consistent with this, the full-length protein is required for maximal inhibition of osteoblast differentiation and osteoclast activation, although the isolated Link module retains significant activity in the latter case. We hypothesize that TSG-6 has dual roles in bone remodeling; one protective, where it inhibits RANKL-induced bone erosion in inflammatory diseases such as arthritis, and the other homeostatic, where its interactions with BMP-2 and RANKL help to balance mineralization by osteoblasts and bone resorption by osteoclasts.