Prostate-specific antigen stimulates osteoprotegerin production and inhibits receptor activator of nuclear factor-kappaB ligand expression by human osteoblasts
Prostate-specific antigen stimulates osteoprotegerin production and inhibits receptor activator of nuclear factor-kappaB ligand expression by human osteoblasts
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DOI：
10.1002/pros.20574
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发表时间：
2007-06-01
期刊：
影响因子：
2.8
通讯作者：
Tachibana, Masaaki
中科院分区：
文献类型：
--
作者：
Yonou, Hiroyuki;Horiguchi, Yutaka;Tachibana, Masaaki
背景前列腺癌细胞产生大量的前列腺特异性抗原（PSA），其被广泛用作这种癌症的标志物。尽管它被广泛用于前列腺癌的诊断，但PSA在骨转移中的病理生理作用的许多方面仍然不清楚。核因子-κ B配体受体激活剂（RANKL）对破骨细胞的活化至关重要，而骨保护素（OPG）可中和RANKL的作用。作用于骨的各种物质已被证明可调节成骨细胞RANKL和OPG的产生。在这项研究中，我们研究了PSA对人成骨样细胞OPG和RANKL mRNA表达以及蛋白质产生的影响。加入PSA培养72 h后，MG-63和SaOS-2细胞OPG mRNA表达和蛋白分泌呈浓度依赖性增加。当成骨细胞与PSA（100 ng/ml）孵育时，OPG mRNA表达和蛋白分泌随时间的推移而增加。α（1）-抗糜蛋白酶（ACT）可抑制PSA的丝氨酸蛋白酶活性，抑制PSA引起的CPG mRNA表达和蛋白质产量的增加，抗转化生长因子-β抗体也可抑制PSA的这种作用。基于我们的研究结果，PSA通过其自身的丝氨酸蛋白酶活性作用于人成骨样细胞并促进成骨细胞分化。此外，PSA刺激成骨细胞的OPG产生并抑制RANKL表达，并抑制破骨细胞的骨吸收，表明其有助于前列腺癌骨转移的成骨细胞特征。
BACKGROUND. Prostate cancer cells produce a large amount of prostate-specific antigen (PSA), which is widely used as a marker for this cancer. Even though it is widely used in the diagnosis of prostate cancer, many aspects of the pathophysiologic role of PSA in bone metastasis remain obscure. The receptor activator of nuclear factor-kappa B ligand (RANKL) is essential for the activation of osteoclasts, while osteoprotegerin (OPG) neutralizes the action of RANKL. Various substances that act on bone have been shown to modulate the production of RANKL and OPG by osteoblasts.METHODS. In this study, we investigated the effect of PSA on the expression of OPG and RANKL mRNA and on protein production in human osteoblast-like cells.RESULTS. After addition of PSA and culture for 72 h, OPG mRNA expression and protein secretion by MG-63 and SaOS-2 cells showed a concentration-dependent increase. When osteoblasts were incubated with PSA (100 ng/ml), OPG mRNA expression and protein secretion increased with the passage of time. alpha(1)-antichymotrypsin (ACT), which inactivates the serine protease activity of PSA, inhibited the increase of CPG mRNA expression and protein production in response to PSA, and this effect of PSA was also inhibited by anti-transforming growth factor-beta antibody.CONCLUSIONS. Based on our findings, PSA acts on human osteoblast-like cells via its own serine protease activity and promotes osteoblast differentiation. In addition, PSA stimulates OPG production and inhibits RANKL expression of osteoblasts, and inhibits bone resorption by osteoclasts, suggesting that it contributes to the characteristic osteoblastic features of bone metastases of prostate cancer.