The phosphoinositide 3-kinase isoform PI3Kβ regulates osteoclast-mediated bone resorption in humans and mice.
The phosphoinositide 3-kinase isoform PI3Kβ regulates osteoclast-mediated bone resorption in humans and mice.
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DOI：
10.1002/art.38660
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发表时间：
2014-08
影响因子：
13.3
通讯作者：
Mocsai, Attila
中科院分区：
文献类型：
--
作者：
Gyori, David;Csete, Daniel;Benko, Szilvia;Kulkarni, Suhasini;Mandl, Peter;Dobo-Nagy, Csaba;Vanhaesebroeck, Bart;Stephens, Len;Hawkins, Phillip T.;Mocsai, Attila
虽然磷脂酰肌醇3-激酶(PI3K)参与了多种细胞内信号转导过程，但不同PI3K亚型的具体功能尚不清楚。我们之前已经证明，在K/BxN血清转移模型中，PI3Kβ亚型是关节炎发生所必需的。由于破骨细胞在炎性关节炎和其他疾病的病理性骨丢失中起关键作用，我们开展了这项研究，通过遗传学和药理学相结合的方法来测试PI3Kβ在破骨细胞发育和功能中的作用。用PI3Kβ选择性抑制剂TGX221和PI3Kβ小鼠检测PI3Kβ−/−在原代培养的人和小鼠破骨细胞中的作用。用显微计算机断层扫描和组织形态计量学分析评价PI3Kβ−/−小鼠的骨小梁结构。在体外破骨细胞分化过程中，PI3Kβ的表达明显上调。PI3Kβ抑制剂TGX221或PI3Kβ的遗传缺陷可显著降低人或小鼠祖细胞体外多核破骨细胞的发育及其吸收能力。这可能是由于PI3Kβ−/−小鼠多核细胞不能形成肌动蛋白环，并保留了细胞内的酸性小泡和组织蛋白K，这可能是由于细胞骨架重组和囊泡运输缺陷所致。相反，破骨细胞特异性基因的表达和破骨细胞的存活和凋亡没有受到影响。PI3Kβ−/−小鼠骨小梁体积明显增大，破骨细胞形态异常，吸收陷窝形成缺陷。PI3Kβ在破骨细胞的发育和功能中起重要作用，是体内骨稳态所必需的。
While phosphoinositide 3-kinases (PI3Ks) are involved in various intracellular signal transduction processes, the specific functions of the different PI3K isoforms are poorly understood. We have previously shown that the PI3Kβ isoform is required for arthritis development in the K/BxN serum–transfer model. Since osteoclasts play a critical role in pathologic bone loss during inflammatory arthritis and other diseases, we undertook this study to test the role of PI3Kβ in osteoclast development and function using a combined genetic and pharmacologic approach. The role of PI3Kβ in primary human and murine osteoclast cultures was tested with the PI3Kβ-selective inhibitor TGX221 and by using PI3Kβ−/− mice. The trabecular bone architecture of PI3Kβ−/− mice was evaluated using micro–computed tomography and histomorphometric analyses. The expression of PI3Kβ was strongly and specifically up-regulated during in vitro osteoclast differentiation. In vitro development of large multinucleated osteoclasts from human or murine progenitors and their resorption capacity were strongly reduced by the PI3Kβ inhibitor TGX221 or by the genetic deficiency of PI3Kβ. This was likely due to defective cytoskeletal reorganization and vesicular trafficking, since PI3Kβ−/− mouse multinucleated cells failed to form actin rings and retained intracellular acidic vesicles and cathepsin K. In contrast, osteoclast-specific gene expression and the survival and apoptosis of osteoclasts were not affected. PI3Kβ−/− mice had significantly increased trabecular bone volume and showed abnormal osteoclast morphology with defective resorption pit formation. PI3Kβ plays an important role in osteoclast development and function and is required for in vivo bone homeostasis.
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影响因子：
4.4
作者：
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通讯作者：
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通讯作者：
Mocsai, Attila