Ishii Masaru, Egen Jackson G, Klauschen Frederick, Meier-Schellersheim Martin, Saeki Yukihiko, Vacher Jean, Proia Richard L, Germain Ronald N
Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892, USA.
Nature. 2009 Mar 26;458(7237):524-8. doi: 10.1038/nature07713. Epub 2009 Feb 8.
Osteoclasts are the only somatic cells with bone-resorbing capacity and, as such, they have a critical role not only in normal bone homeostasis (called 'bone remodelling') but also in the pathogenesis of bone destructive disorders such as rheumatoid arthritis and osteoporosis. A major focus of research in the field has been on gene regulation by osteoclastogenic cytokines such as receptor activator of NF-kappaB-ligand (RANKL, also known as TNFSF11) and TNF-alpha, both of which have been well documented to contribute to osteoclast terminal differentiation. A crucial process that has been less well studied is the trafficking of osteoclast precursors to and from the bone surface, where they undergo cell fusion to form the fully differentiated multinucleated cells that mediate bone resorption. Here we report that sphingosine-1-phosphate (S1P), a lipid mediator enriched in blood, induces chemotaxis and regulates the migration of osteoclast precursors not only in culture but also in vivo, contributing to the dynamic control of bone mineral homeostasis. Cells with the properties of osteoclast precursors express functional S1P(1) receptors and exhibit positive chemotaxis along an S1P gradient in vitro. Intravital two-photon imaging of bone tissues showed that a potent S1P(1) agonist, SEW2871, stimulated motility of osteoclast precursor-containing monocytoid populations in vivo. Osteoclast/monocyte (CD11b, also known as ITGAM) lineage-specific conditional S1P(1) knockout mice showed osteoporotic changes due to increased osteoclast attachment to the bone surface. Furthermore, treatment with the S1P(1) agonist FTY720 relieved ovariectomy-induced osteoporosis in mice by reducing the number of mature osteoclasts attached to the bone surface. Together, these data provide evidence that S1P controls the migratory behaviour of osteoclast precursors, dynamically regulating bone mineral homeostasis, and identifies a critical control point in osteoclastogenesis that may have potential as a therapeutic target.
破骨细胞是唯一具有骨吸收能力的体细胞，因此，它们不仅在正常骨稳态（称为“骨重塑”）中起关键作用，而且在类风湿性关节炎和骨质疏松症等骨破坏性疾病的发病机制中也起关键作用。该领域的主要研究重点一直是破骨细胞生成细胞因子如核因子κB受体活化因子配体（RANKL，也称为TNFSF11）和肿瘤坏死因子α对基因的调控，这两种细胞因子均已被充分证明有助于破骨细胞的终末分化。一个研究较少的关键过程是破骨细胞前体往返于骨表面的运输，在骨表面它们进行细胞融合以形成介导骨吸收的完全分化的多核细胞。在此，我们报告，富含于血液中的脂质介质鞘氨醇-1-磷酸（S1P）不仅在培养中而且在体内诱导趋化性并调节破骨细胞前体的迁移，有助于骨矿物质稳态的动态控制。具有破骨细胞前体特性的细胞表达功能性S1P(1)受体，并在体外沿S1P梯度表现出正向趋化性。骨组织的活体双光子成像显示，一种强效S1P(1)激动剂SEW2871在体内刺激了含破骨细胞前体的单核细胞群体的运动。破骨细胞/单核细胞（CD11b，也称为ITGAM）谱系特异性条件性S1P(1)基因敲除小鼠由于破骨细胞与骨表面的附着增加而出现骨质疏松性改变。此外，用S1P(1)激动剂FTY720治疗可通过减少附着在骨表面的成熟破骨细胞数量来缓解小鼠去卵巢诱导的骨质疏松症。总之，这些数据提供了证据，表明S1P控制破骨细胞前体的迁移行为，动态调节骨矿物质稳态，并确定了破骨细胞生成中的一个关键控制点，该控制点可能具有作为治疗靶点的潜力。
