Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3.
Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3.
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DOI：
10.1002/jbmr.3945
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发表时间：
2020-04
期刊：
影响因子：
--
通讯作者：
Lee SK
中科院分区：
文献类型：
--
作者：
Shin B;Kupferman J;Schmidt E;Polleux F;Delany AM;Lee SK
在RANKL诱导的破骨细胞形成过程中，rac1特异性GTPase激活蛋白Sit-Robo GAP2(SRGAP2)显著上调。SRGAP2与细胞膜相互作用，局部抑制rac1的活性。在这项研究中，我们确定了SRGAP2在髓系中对骨稳态的作用以及对肿瘤坏死因子α治疗的破骨反应。采用组织形态分析、体外培养和免疫印迹分析等方法，研究了髓系特异性缺失SRGAP2的小鼠(SRGAP2f/f：LysM-Cre；SRGAP2CKO)的骨表型。用类似的方法确定肿瘤坏死因子α攻击对SRGAP2CKO小鼠破骨细胞形成的影响。雄性SRGAP2 CKO小鼠的骨参数未受影响。然而，雌性CKO小鼠由于成骨细胞表面和骨形成率的增加而显示出更高的骨小梁体积，而破骨细胞参数没有改变。在体外，SRGAP2 CKO细胞强烈地促进了rac1的激活，但RANKL诱导的破骨细胞的形成不受影响。相反，SRGAP2 CKO破骨细胞的条件培养液促进了成骨细胞的分化，并增加了骨合成破骨因子SLIT3的水平，为体内增加骨形成提供了可能的机制。Rac1被炎性细胞因子肿瘤坏死因子α迅速激活。颅上注射肿瘤坏死因子α可引起SRGAP2CKO小鼠破骨反应增强。在体外，SRGAP2 CKO小鼠的细胞显示出对肿瘤坏死因子α的反应增加了破骨细胞的形成。我们得出结论，SRGAP2通过rac1在炎症过程中限制破骨细胞的生成，并限制旁分泌破骨细胞因子SLIT3的表达，SLIT3是骨形成的正向调节因子。
The Rac1-specific GTPase activating protein Slit-Robo GAP2 (Srgap2) is dramatically up regulated during RANKL-induced osteoclastogenesis. Srgap2 interacts with the cell membrane to locally inhibit activity of Rac1. In this study, we determined the role of Srgap2 in the myeloid lineage on bone homeostasis and the osteoclastic response to TNFα treatment. The bone phenotype of mice specifically lacking Srgap2 in the myeloid lineage (Srgap2f/f:LysM-Cre; Srgap2 cKO) was investigated using histomorphomeric analysis, in vitro cultures and western blot analysis. Similar methods were used to determine the impact of TNFα challenge on osteoclast formation in Srgap2 cKO mice. Bone parameters in male Srgap2 cKO mice were unaffected. However, female cKO mice displayed higher trabecular bone volume due to increased osteoblast surface and bone formation rate, while osteoclastic parameters were unaltered. In vitro, cells from Srgap2 cKO had strongly enhanced Rac1 activation, but RANKL-induced osteoclast formation was unaffected. In contrast, conditioned medium from Srgap2 cKO osteoclasts promoted osteoblast differentiation and had increased levels of the bone anabolic clastokine SLIT3, providing a possible mechanism for increased bone formation in vivo. Rac1 is rapidly activated by the inflammatory cytokine TNFα. Supracalvarial injection of TNFα caused an augmented osteoclastic response in Srgap2 cKO mice. In vitro, cells from Srgap2 cKO mice displayed increased osteoclast formation in response to TNFα. We conclude that Srgap2 plays a prominent role in limiting osteoclastogenesis during inflammation through Rac1, and restricts expression of the paracrine clastokine SLIT3, a positive regulator of bone formation.
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影响因子：
4.8
作者：
Chellaiah, MA;Soga, N;Hruska, KA
通讯作者：
Hruska, KA
SRGAP2 人类特异性旁系同源物对 SRGAP2 功能的抑制可在脊柱成熟过程中诱导幼态持续
影响因子：
64.5
作者：
Charrier C;Joshi K;Coutinho-Budd J;Kim JE;Lambert N;de Marchena J;Jin WL;Vanderhaeghen P;Ghosh A;Sassa T;Polleux F
通讯作者：
Polleux F
影响因子：
82.9
作者：
Faccio, R;Teitelbaum, SL;Swat, W
通讯作者：
Swat, W
影响因子：
10.5
作者：
Kant, Shashi;Swat, Wojciech;Davis, Roger J.
通讯作者：
Davis, Roger J.
DOI：
10.1007/978-1-61779-415-5_2
发表时间：
2012-01-01
期刊：
BONE RESEARCH PROTOCOLS, SECOND EDITION
影响因子：
--
作者：
Bakker, Astrid D.;Klein-Nulend, Jenneke
通讯作者：
Klein-Nulend, Jenneke