Molecular Mechanism of the Bifunctional Role of Lipopolysaccharide in Osteoclastogenesis
Molecular Mechanism of the Bifunctional Role of Lipopolysaccharide in Osteoclastogenesis
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DOI：
10.1074/jbc.m809789200
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发表时间：
2009-05-01
影响因子：
4.8
通讯作者：
Feng, Xu
中科院分区：
文献类型：
--
作者：
Liu, Jianzhong;Wang, Shunqing;Feng, Xu
脂多糖（Lipopolysaccharide，LPS）是一种常见的细菌衍生产物，长期以来被认为是牙周骨丢失的关键因素。然而，LPS诱导骨丢失的确切细胞和分子机制仍然存在争议。在这里，我们发现LPS抑制了新鲜分离的破骨细胞前体的破骨细胞生成，但刺激了体外组织培养皿、骨切片和含成骨细胞的共培养系统中RANKL预处理的破骨细胞形成，表明RANKL介导的谱系定型是LPS诱导的破骨细胞生成的先决条件。此外，RANKL介导的谱系定型是长期的、不可逆的和TLR 4依赖性的。LPS主要通过调节NFATc 1（破骨细胞生成的主要调节因子）的表达发挥双重功能，因为它在新鲜分离的破骨细胞前体中消除了RANKL诱导的NFATc 1表达，但在RANKL预处理的细胞中刺激其表达。此外，LPS通过激活Akt、NF-κ B和ERK通路延长破骨细胞存活。我们目前的工作不仅明确了LPS在破骨细胞发生中的作用，而且阐明了其在破骨细胞形成和存活中复杂功能的分子机制，从而为将来阐明牙周骨丢失的确切机制奠定了基础。
Lipopolysaccharide (LPS), a common bacteria-derived product, has long been recognized as a key factor implicated in periodontal bone loss. However, the precise cellular and molecular mechanisms by which LPS induces bone loss still remains controversial. Here, we show that LPS inhibited osteoclastogenesis from freshly isolated osteoclast precursors but stimulated osteoclast formation from those pretreated with RANKL in vitro in tissue culture dishes, bone slices, and a co-culture system containing osteoblasts, indicating that RANKL-mediated lineage commitment is a prerequisite for LPS-induced osteoclastogenesis. Moreover, the RANKL-mediated lineage commitment is long term, irreversible, and TLR4-dependent. LPS exerts the dual function primarily by modulating the expression of NFATc1, a master regulator of osteoclastogenesis, in that it abolished RANKL-induced NFATc1 expression in freshly isolated osteoclast precursors but stimulated its expression in RANKL-pretreated cells. In addition, LPS prolonged osteoclast survival by activating the Akt, NF-kappa B, and ERK pathways. Our current work has not only unambiguously defined the role of LPS in osteoclastogenesis but also has elucidated the molecular mechanism underlying its complex functions in osteoclast formation and survival, thus laying a foundation for future delineation of the precise mechanism of periodontal bone loss.