Chemorepulsion by blood S1P regulates osteoclast precursor mobilization and bone remodeling in vivo.
Chemorepulsion by blood S1P regulates osteoclast precursor mobilization and bone remodeling in vivo.
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DOI：
10.1084/jem.20101474
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发表时间：
2010-12-20
期刊：
影响因子：
--
通讯作者：
Germain RN
中科院分区：
文献类型：
--
作者：
Ishii M;Kikuta J;Shimazu Y;Meier-Schellersheim M;Germain RN
破骨细胞前体的趋化性和化学排斥依赖于S1 P浓度和受体S1 PR 1和S1 PR 2的表达，其作用是调节破骨细胞前体定位。鞘氨醇-1-磷酸（S1 P）是一种富含于血液中的脂质介质，部分通过S1 P受体1（S1 PR 1）控制破骨细胞（OC）前体（OP）在血液和骨之间的动态迁移，该受体1（S1 PR 1）指导对S1 P的正趋化。我们发现，OP也表达S1 PR 2，S1 P受体介导的负趋化性（或化学排斥）。OP阳性趋化性是突出的梯度与低的最大浓度的S1 P，而这种行为是最小的领域与高的最大S1 P浓度。这种反向行为是由S1 PR 2介导的化学排斥作用引起的，其作用是覆盖S1 PR 1的顺向运动。S1 PR 2-缺陷小鼠表现出中度骨硬化症的骨吸收减少的结果，表明S1 PR 2有助于OP定位在骨上介导的化学排斥远离血液中的S1 P水平高。拮抗剂JTE 013抑制S1 PR 2功能改变了单核细胞样细胞（包括OP）的迁移行为，并通过限制OP定位和减少附着在骨表面的成熟OC数量来缓解小鼠模型中的骨质疏松症。因此，S1 P依赖性趋化性的相互调节通过精细调节OP定位来控制骨重建。这一调节轴可能是有前途的，作为一个治疗目标的疾病影响OC依赖性骨重建。
Chemotaxis and chemorepulsion of osteoclast precursors depends on S1P concentrations and expression of the receptors S1PR1 and S1PR2, which act to regulate osteoclast precursor localization. Sphingosine-1-phosphate (S1P), a lipid mediator enriched in blood, controls the dynamic migration of osteoclast (OC) precursors (OPs) between the blood and bone, in part via the S1P receptor 1 (S1PR1) which directs positive chemotaxis toward S1P. We show that OPs also express S1PR2, an S1P receptor which mediates negative chemotaxis (or chemorepulsion). OP-positive chemotaxis is prominent in gradients with low maximal concentrations of S1P, whereas such behavior is minimal in fields with high maximal S1P concentrations. This reverse-directional behavior is caused by S1PR2-mediated chemorepulsion acting to override S1PR1 upgradient motion. S1PR2-deficient mice exhibit moderate osteopetrosis as a result of a decrease in osteoclastic bone resorption, suggesting that S1PR2 contributes to OP localization on the bones mediated by chemorepulsion away from the blood where S1P levels are high. Inhibition of S1PR2 function by the antagonist JTE013 changed the migratory behavior of monocytoid cells, including OPs, and relieved osteoporosis in a mouse model by limiting OP localization and reducing the number of mature OCs attached to the bone surface. Thus, reciprocal regulation of S1P-dependent chemotaxis controls bone remodeling by finely regulating OP localization. This regulatory axis may be promising as a therapeutic target in diseases affecting OC-dependent bone remodeling.
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影响因子：
5.3
作者：
Jung, S;Aliberti, J;Littman, DR
通讯作者：
Littman, DR
影响因子：
6.2
作者：
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影响因子：
20.3
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影响因子：
14.8
作者：
Klauschen, Frederick;Ishii, Masaru;Meier-Schellersheim, Martin
通讯作者：
Meier-Schellersheim, Martin
DOI：
10.1016/s0006-291x(02)02671-2
发表时间：
2002-12-06
影响因子：
3.1
作者：
Osada, M;Yatomi, Y;Ozaki, Y
通讯作者：
Ozaki, Y