Prostate transmembrane protein androgen induced 1 is induced by activation of osteoclasts and regulates bone resorption
Prostate transmembrane protein androgen induced 1 is induced by activation of osteoclasts and regulates bone resorption
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DOI：
10.1096/fj.201801573r
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发表时间：
2019-03
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通讯作者：
Xianghe Xu;Hirohito Hirata;M. Shiraki;Asana Kamohara;K. Nishioka;H. Miyamoto;T. Kukita;A. Kukita
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作者：
Xianghe Xu;Hirohito Hirata;M. Shiraki;Asana Kamohara;K. Nishioka;H. Miyamoto;T. Kukita;A. Kukita
破骨细胞来源于造血细胞，在骨表面活化。破骨细胞通过膜转运释放酸和溶酶体酸水解酶，吸收骨。前列腺跨膜蛋白雄激素诱导1（Pmepa 1）是调节癌细胞增殖、迁移和转移的I型跨膜蛋白。由于最近的报道表明Pmepa 1参与癌细胞的膜转运，我们研究了Pmepa 1在破骨细胞功能中的作用。pmepa 1的表达在体外塑料表面上形成的破骨细胞中几乎没有检测到，但在钙化基质上形成的活化破骨细胞中明显增加。骨吸收抑制剂，如阿仑膦酸钠，巴弗洛霉素A1，和PI 3 K抑制剂LY 294002，抑制破骨细胞中Pmepa 1的表达。Pmepa 1表达的敲低损害了骨吸收活性，并抑制了对破骨细胞功能至关重要的环状富含肌动蛋白的足体带的形成。破骨细胞中pmepa 1蛋白定位于溶酶体。此外，在佐剂诱导的关节炎大鼠中观察到的骨破坏部位，显著高水平的Pmepa 1表达与破骨细胞的骨吸收有关。我们的研究结果表明，Pmepa 1是骨吸收的关键调节因子，是活化破骨细胞的有前途的标志物，也是病理性骨破坏的潜在治疗靶点。徐，X.，Hirata，H.，Shiraki，M.，Kamohara，A.，Nishioka，K.，Miyamoto，H.，Kukita，T.，Kukita，A.前列腺跨膜蛋白雄激素诱导1是通过激活破骨细胞诱导的，并调节骨吸收。FASEB J. 33，4365-4375（2019）。www.fasebj.org
Osteoclasts derived from hematopoietic cells are activated on bone surface. To resorb bone, osteoclasts release acid and lysosome acid hydrolase via membrane transport. Prostate transmembrane protein androgen induced 1 (Pmepa1) is a type I transmembrane protein that regulates proliferation, migration, and metastasis of cancer cells. Because recent reports showed that Pmepa1 is involved in membrane transport in cancer cells, we investigated the role of Pmepa1 in osteoclast function. Pmepa1 expression was barely detected in osteoclasts formed on plastic surfaces in vitro, but was markedly increased in activated osteoclasts formed on calcified matrix. Inhibitors of bone resorption, such as alendronate, bafilomycin A1, and the PI3K inhibitor LY294002, suppressed the expression of Pmepa1 in osteoclasts. Knockdown of Pmepa1 expression impaired bone resorption activity and inhibited formation of a ring‐like, actin‐rich podosome belt that is essential for osteoclast function. Pmepa1 protein localized to lysosomes in osteoclasts. In addition, in sites of bone destruction observed in rats with adjuvant‐induced arthritis, a marked high level of Pmepa1 expression was associated with the osteoclasts' resorbing bone. Our results suggest that Pmepa1 is a critical regulator of bone resorption and is a promising marker for activated osteoclasts and a potential therapeutic target in pathologic bone destruction.—Xu, X., Hirata, H., Shiraki, M., Kamohara, A., Nishioka, K., Miyamoto, H., Kukita, T., Kukita, A. Prostate transmembrane protein androgen induced 1 is induced by activation of osteoclasts and regulates bone resorption. FASEB J. 33, 4365–4375 (2019). www.fasebj.org