Marrow stromal cells and osteoclast precursors differentially contribute to TNF-α-induced osteoclastogenesis in vivo
Marrow stromal cells and osteoclast precursors differentially contribute to TNF-α-induced osteoclastogenesis in vivo
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DOI：
10.4049/jimmunol.173.8.4838
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发表时间：
2004-10-15
影响因子：
4.4
通讯作者：
Teitelbaum, SL
中科院分区：
文献类型：
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作者：
Kitaura, H;Sands, MS;Teitelbaum, SL
骨髓基质细胞是关键的破骨细胞因子受体激活剂 NF-κB (RANK) 配体 (RANKL) 的主要来源。为了个体化骨髓基质细胞在体内TNF-α驱动的破骨细胞形成的不同状态中的作用，我们产生了嵌合小鼠，其中将T细胞和基质细胞免疫耗尽的野生型（WT）骨髓移植到删除了p55和p75 TNFR的致命辐射小鼠中。作为对照，将类似处理的 WT 骨髓移植到 WT 小鼠中。每组都给予递增剂量的TNF-α。无论体内 TNF-α 治疗或受体动物是否拥有 TNF-α 反应性基质细胞，离体暴露于高剂量细胞因子都会诱导旺盛的破骨细胞生成。相反，用低剂量TNF-α处理的骨髓的破骨能力需要体内携带TNFR的基质细胞的启动。重要的是，体内细胞因子反应性基质细胞的破骨作用随着TNF-α剂量的增加而减弱。与这一结论一致，患有严重炎症性关节炎的小鼠会发生严重的破骨细胞生成和骨侵蚀，与基质细胞的 TNFR 表达无关。 TNF-α 直接诱导破骨细胞募集的特点是 RANK 表达增强和前体细胞对 RANKL 敏感。因此，伴随环境TNF-α相对适度升高的骨质溶解取决于反应性基质细胞。或者，在严重的关节周围炎症状态下，TNF-α可以通过不依赖于细胞因子反应性基质细胞和T淋巴细胞直接促进破骨细胞前体细胞的分化来充分发挥其骨侵蚀作用。
The marrow stromal cell is the principal source of the key osteoclastogenic cytokine receptor activator of NF-kappaB (RANK) ligand (RANKL). To individualize the role of marrow stromal cells in varying states of TNF-alpha-driven osteoclast formation in vivo, we generated chimeric mice in which wild-type (WT) marrow, immunodepleted of T cells and stromal cells, is transplanted into lethally irradiated mice deleted of both the p55 and p75 TNFR. As control, similarly treated WT marrow was transplanted into WT mice. Each group was administered increasing doses of TNF-alpha. Exposure to high-dose cytokine ex vivo induces exuberant osteoclastogenesis irrespective of in vivo TNF-alpha treatment or whether the recipient animals possess TNF-alpha-responsive stromal cells. In contrast, the osteoclastogenic capacity of marrow treated with lower-dose TNF-alpha requires priming by TNFR-bearing stromal cells in vivo. Importantly, the osteoclastogenic contribution of cytokine responsive stromal cells in vivo diminishes as the dose of TNF-alpha increases. In keeping with this conclusion, mice with severe inflammatory arthritis develop profound osteoclastogenesis and bone erosion independent of stromal cell expression of TNFR. The direct induction of osteoclast recruitment by TNF-alpha is characterized by enhanced RANK expression and sensitization of precursor cells to RANKL. Thus, osteolysis attending relatively modest elevations in ambient TNF-alpha depends upon responsive stromal cells. Alternatively, in states of severe periarticular inflammation, TNF-alpha may fully exert its bone erosive effects by directly promoting the differentiation of osteoclast precursors independent of cytokine-responsive stromal cells and T lymphocytes.