Cytosolic protein tyrosine phosphatase epsilon (cyt-PTPε) plays a central role in controlling differentiation and function of osteoclasts, whose overactivation causes osteoporosis. Based on our previous study reporting a number of cyt-PTPε inhibitory chemical compounds, we carried out a further and extended analysis of our compounds to examine their effects on cyt-PTPε-mediated dephosphorylation and on osteoclast organization and differentiation. Among five compounds showing target selectivity to cyt-PTPε over three other phosphatases in vitro, two compounds exhibited an inhibitory effect against the dephosphorylation of cellular Src protein, the cyt-PTPε substrate. Moreover, these two compounds caused destabilization of the podosome structure that is necessary for the bone-resorbing activity of osteoclasts, and also attenuated cellular differentiation of monocytes into osteoclasts, without affecting cell viability. Therefore, these findings not only verified anti-osteoclastic effects of our cyt-PTPε inhibitory compounds, but also showed that cyt-PTPε expressed in osteoclasts could be a putative therapeutic target worth considering.

胞质蛋白酪氨酸磷酸酶ε（cyt-PTPε）在控制破骨细胞的分化和功能中起着核心作用，破骨细胞的过度活化会导致骨质疏松。基于我们先前的报告，该研究报告了许多cyt-PTPε抑制性化合物，我们对我们的化合物进行了进一步的扩展分析，以检查它们对cyt-PTPε介导的去磷酸化以及破骨细胞组织和分化的影响。在5种化合物中对体外其他3种磷酸酶显示对cyt-PTPε的靶标选择性，两种化合物均表现出对细胞Src蛋白（cyt-PTPε底物）去磷酸化的抑制作用。而且，这两种化合物引起破骨细胞结构的不稳定，这是破骨细胞的骨吸收活性所必需的，并且还减弱了单核细胞向破骨细胞的细胞分化，而不影响细胞活力。因此，这些发现不仅验证了我们的cyt-PTPε抑制化合物的抗破骨作用，而且表明破骨细胞中表达的cyt-PTPε可能是值得考虑的治疗靶标。