Osteoclastic bone resorption through receptor tyrosine kinase and extracellular signal-regulated kinase signaling in mature osteoclasts.
Osteoclastic bone resorption through receptor tyrosine kinase and extracellular signal-regulated kinase signaling in mature osteoclasts.
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DOI：
10.1007/s10165-003-0257-2
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发表时间：
2004-01-01
影响因子：
2.2
通讯作者：
Chikazu, Daichi
中科院分区：
文献类型：
--
作者：
Kawaguchi, Hiroshi;Katagiri, Mika;Chikazu, Daichi
最近的研究表明，通过在成熟破骨细胞上表达的受体酪氨酸激酶（RTK）的信号传导参与骨细胞的骨吸收。本研究探讨了成熟破骨细胞上表达的两种主要RTK的作用和机制，即成纤维细胞生长因子受体1（FGFR 1）和Tyro 3。在FGF受体（FGFR 1 -4）中，仅在分离的小鼠破骨细胞上检测到FGFR 1，而在小鼠成骨细胞上鉴定出所有FGFR。Tyro 3仅见于骨细胞中成熟的破骨细胞。FGF-2在低浓度（>==10（-12）M）下适度刺激分离的兔破骨细胞的小窝形成，而在高浓度（>=10（-9）M）下强烈刺激未分级骨细胞的小窝形成。Gas 6是Tyro 3的配体，在骨细胞中广泛表达，并刺激破骨细胞功能在牙本质切片上形成吸收小凹。在小鼠破骨细胞中，FGF-2和Gas 6均上调细胞蛋白的磷酸化，包括细胞外信号调节激酶（ERK），并分别增加免疫沉淀的FGFR 1和Tyro 3的激酶活性。这些细胞因子对小鼠和兔破骨细胞功能的刺激被ERK的特异性抑制剂PD 98059消除。这些结果有力地表明，这些细胞因子通过激活RTK和ERK直接作用于成熟的破骨细胞，引起骨吸收的刺激。
It has recently been suggested that signaling through receptor tyrosine kinases (RTKs) expressed on mature osteoclasts is involved in osteoclastic bone resorption. This study investigated the role and mechanism of two major RTKs expressed on mature osteoclasts, fibroblast growth factor receptor type 1 (FGFR1) and Tyro 3. Among the FGF receptors (FGFR1-4), only FGFR1 was detected on isolated mouse osteoclasts, while all FGFRs were identified on mouse osteoblasts. Tyro 3 was seen only in mature osteoclasts among bone cells. FGF-2 moderately stimulated pit formation by isolated rabbit osteoclasts at low concentrations (>==10(-12) M), whereas at high concentrations (>==10(-9) M) it strongly stimulated pit formation by unfractionated bone cells. Gas6, the ligand of Tyro 3, was expressed ubiquitously in bone cells and stimulated osteoclast function to form resorbed pits on a dentine slice. Both FGF-2 and Gas6 upregulated the phosphorylation of cellular proteins, including extracellular signal-regulated kinase (ERK), and increased the kinase activity of immunoprecipitated FGFR1 and Tyro 3, respectively, in mouse osteoclasts. The stimulation of these cytokines on mouse and rabbit osteoclast functions was abrogated by PD98059, a specific inhibitor of ERK. These results strongly suggest that these cytokines act directly on mature osteoclasts through the activation of RTKs and ERK, causing the stimulation of bone resorption.