Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea; and.
Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
J Immunol. 2018 Apr 1;200(7):2455-2463. doi: 10.4049/jimmunol.1700582. Epub 2018 Feb 12.
The non-receptor tyrosine kinase c-Src participates in bone metabolism by regulating the activities of both the bone-resorbing osteoclasts and bone-forming osteoblasts. In this study, we investigated whether megakaryocyte-associated tyrosine kinase (Matk), a potent inhibitor of c-Src, affects the functions of murine osteoclasts and osteoblasts. Results revealed that the formation of osteoclasts with actin rings was attenuated by Matk overexpression in osteoclast precursor cells but was enhanced by Matk knockdown. The inhibitory effect of Matk on osteoclasts was closely related with the inhibition of c-Src activity. Intriguingly, Matk overexpression in osteoblasts reduced bone nodule formation. Conversely, Matk knockdown increased osteoblast function. Most importantly, binding of Matk to Runx2 resulted in the inhibition of Runx2 translocation into the nucleus and downregulation of Runx2 target genes. Taken together, our findings demonstrated that Matk plays a critical role in bone metabolism by impairing the functions of osteoclasts and osteoblasts via distinct mechanisms involving inhibition of c-Src-dependent and -independent signaling pathways.
非受体酪氨酸激酶 c-Src 通过调节骨吸收破骨细胞和骨形成成骨细胞的活性参与骨代谢。在这项研究中，我们研究了巨核细胞相关酪氨酸激酶 (Matk)，一种 c-Src 的有效抑制剂，是否影响小鼠破骨细胞和成骨细胞的功能。结果表明，Matk 在破骨细胞前体细胞中的过表达减弱了具有肌动蛋白环的破骨细胞的形成，但 Matk 的敲低增强了其形成。Matk 对破骨细胞的抑制作用与 c-Src 活性的抑制密切相关。有趣的是，Matk 在成骨细胞中的过表达减少了骨结节的形成。相反，Matk 的敲低增加了成骨细胞的功能。最重要的是，Matk 与 Runx2 的结合导致 Runx2 向核内易位和 Runx2 靶基因的下调受到抑制。总之，我们的研究结果表明，Matk 通过涉及抑制 c-Src 依赖性和非依赖性信号通路的不同机制，通过损害破骨细胞和成骨细胞的功能，在骨代谢中发挥关键作用。
