Lipopolysaccharide-induced osteoclastogenesis in Src homology 2-domain phosphatase-1-deficient viable motheaten mice
Lipopolysaccharide-induced osteoclastogenesis in Src homology 2-domain phosphatase-1-deficient viable motheaten mice
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DOI：
10.1210/en.2004-0172
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发表时间：
2004-06-01
期刊：
影响因子：
4.8
通讯作者：
Yamazaki, H
中科院分区：
文献类型：
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作者：
Hayashi, S;Tsuneto, M;Yamazaki, H
破骨细胞是参与骨吸收和重塑的造血细胞。核因子-κB 配体受体激活剂 (RANKL) 和巨噬细胞集落刺激因子 (M-CSF) 对于破骨细胞的发育至关重要。 Toll 样受体 (TLR) 家族与 RANK 共享一些下游信号传导。据报道，TLR4 配体脂多糖 (LPS) 可加速骨溶解；然而，从未有报道称，在没有 RANKL 的情况下，通过 TLR 发出的信号可以诱导破骨细胞生成。在这项研究中，我们发现，在存在 M-CSF 和 LPS 且不添加 RANKL 的情况下，蛋白酪氨酸磷酸酶 Src 同源 2 结构域磷酸酶-l 缺陷型 Hcph(me-v)/Hcph(me-v) (me(v)/me(v)) 骨髓细胞产生大量成熟破骨细胞。这种 M-CSF 加 LPS 诱导的破骨细胞生成不受抗 TNFα 拮抗抗体或骨保护素（RANKL 的诱饵受体）的抑制。 TLR 配体对 RANKL 的取代仅发生在 LPS 中。其他配体，例如 TLR2 的肽聚糖或 TLR9 的未甲基化 CpG 寡核苷酸，不支持破骨细胞的生成。破骨细胞前体以及 RANKL 反应性破骨细胞前体存在于骨髓细胞的 Kit 阳性细胞富集部分中。尽管 me(v)/me(v) 骨髓细胞需要与野生型细胞相当浓度的 RANKL 或 TNFα 来启动破骨细胞生成，但在 M-CSF 存在的情况下，mev/mev 骨髓培养物中多核破骨细胞的数量会因同等剂量的 RANKL 或 TNFα 显着增加。这些结果表明，Src同源2-结构域磷酸酶-1功能的缺陷不仅通过RANKL/RANK加速生理性破骨细胞的发育，而且通过LPS获得破骨细胞生成的新途径。
Osteoclasts are hemopoietic cells that participate in bone resorption and remodeling. Receptor activator of nuclear factor-kappaB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) are critical for development of osteoclasts. The Toll-like receptor (TLR) family shares some of the downstream signaling with RANK. The TLR4 ligand, lipopolysaccharide (LPS), is reported to accelerate bone lysis; however, signaling via TLRs has never been reported to induce osteoclastogenesis without RANKL. In this study we showed that significant numbers of mature osteoclasts were generated from protein tyrosine phosphatase Src homology 2-domain phosphatase-l-defective Hcph(me-v)/Hcph(me-v) (me(v)/me(v)) bone marrow cells in the presence of M-CSF and LPS without addition of RANKL in culture. This M-CSF plus LPS-induced osteoclastogenesis was not inhibited by an anti-TNFalpha antagonistic antibody or by osteoprotegerin, a decoy receptor for RANKL. The replacement of RANKL by TLR ligands only occurred with LPS. Other ligands, a peptidoglycan for TLR2 or an unmethylated CpG oligonucleotide for TLR9, did not support osteoclast generation. The osteoclast precursors as well as RANKL-responsive osteoclast precursors were present in the Kit-positive cell-enriched fraction of bone marrow cells. Although me(v)/me(v) bone marrow cells required a comparable concentration of RANKL or TNFalpha as wild-type cells for the initiation of osteoclastogenesis, the numbers of multinucleated osteoclasts in mev/mev bone marrow cultures were significantly increased by the equivalent dose of RANKL or TNFalpha in the presence of M-CSF. These results indicate that a defect of Src homology 2-domain phosphatase-1 function not only accelerates physiological osteoclast development by RANKL/RANK, but also acquires a novel pathway for osteoclastogenesis by LPS.