Tyro 3 receptor tyrosine kinase and its ligand, Gas6, stimulate the function of osteoclasts
Tyro 3 receptor tyrosine kinase and its ligand, Gas6, stimulate the function of osteoclasts
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DOI：
10.1002/stem.160229
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发表时间：
1998-01-01
期刊：
影响因子：
5.2
通讯作者：
Suda, T
中科院分区：
文献类型：
--
作者：
Nakamura, YS;Hakeda, Y;Suda, T
骨是不断形成和吸收的，这一过程是通过两种细胞类型的精确协调来完成的：成骨细胞和破骨细胞。破骨细胞是大的、多核细胞，其来源于与巨噬细胞相同的造血前体，然而，这些骨吸收细胞由于相对不易接近而难以直接研究。利用破骨细胞的粘附特性，从兔骨中分离纯化出破骨细胞，为研究破骨细胞分子提供了机会。我们用聚合酶链反应（PCR）检测了破骨细胞受体酪氨酸激酶的表达，发现在PCR克隆中，Tyro 3经常从破骨细胞中鉴定出来。免疫组化显示Tyro 3在TRAP阳性的多核破骨细胞上表达，而在TRAP阳性的单核细胞上不表达。Tyro 3配体Gas 6在2 ~ 5 min内诱导破骨细胞Tyro 3受体磷酸化。Gas 6和蛋白S直接增强成熟破骨细胞的骨吸收活性，Gas 6的这种作用可被酪氨酸激酶抑制剂除草霉素A所抑制，但Gas 6不影响骨髓细胞破骨细胞的分化。Gas 6和蛋白S依赖于维生素K，维生素K是负责谷氨酸残基羧化的酶的辅因子。这项研究的发现首次表明Gas 6和蛋白S作为骨吸收功能的直接调节剂的新生物活性;它们使人们深入了解这些维生素K依赖性配体在体内骨吸收中的作用。
Bone is continuously being formed and resorbed, This process is accomplished by the precise coordination of two cell types: osteoblasts and osteoclasts, Osteoclasts are large, multinucleated cells that are derived from the same hematopoietic precursors as macrophages, However, these bone-resorbing cells are difficult to study directly because of their relative inaccessibility. The purification of primary osteoclasts from rabbit bones by their adherent nature provides an opportunity for investigating the molecules in osteoclasts, We have examined the expression of receptor tyrosine kinase by polymerase chain reaction (PCR) and found that Tyro 3 was frequently identified from primary osteoclasts in PCR cloning. Immunohistochemistry revealed that Tyro 3 was expressed on the multinucleated osteoclasts which were positive for tartrate-resistant acid phosphatase (TRAP), but not on mononuclear TRAP-positive cells, The Tyro 3 Ligand, Gas6, induced the phosphorylation of Tyro 3 receptors in osteoclasts in two to five min. Gas6 and protein S directly enhanced the bone resorbing activity of mature osteoclasts, This effect of Gas6 was inhibited by the addition of a tyrosine kinase inhibitor, herbimycin A, However, Gas6 did not affect the differentiation of osteoclasts from bone marrow cells. Gas6 and protein S are dependent on vitamin K, a cofactor for the enzyme responsible for carboxylation of glutamic acid residues. The findings in this study are the first to indicate a new biological activity of Gas6 and protein S as a direct regulator of osteoclastic function; they give an insight into the role of these vitamin K-dependent ligands in bone resorption in vivo.