The Src family kinase, Lyn, suppresses osteoclastogenesis in vitro and in vivo
The Src family kinase, Lyn, suppresses osteoclastogenesis in vitro and in vivo
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DOI：
10.1073/pnas.0806963106
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发表时间：
2009-02-17
影响因子：
11.1
通讯作者：
Faccio, Roberta
中科院分区：
文献类型：
--
作者：
Kim, Hyun-Ju;Zhang, Kaihua;Faccio, Roberta
c-Src 激酶是破骨细胞 (OC) 功能的限速激活剂，因此 Src 抑制剂是候选的抗骨质疏松药物。通过影响 alpha nu beta 3 和巨噬细胞集落刺激因子 (M-CSF) 诱导的信号传导，c-Src 对破骨细胞活性至关重要，但对破骨细胞分化不具有重要作用。相反，我们发现 Src 家族激酶 (SFK) 的另一个成员 Lyn 是破骨细胞骨吸收的负调节因子。 Lyn 的缺失增强了 NF-κ B 配体受体激活剂 (RANKL) 介导的破骨细胞前体分化，而不影响增殖和存活，而其过度表达则减少了破骨细胞的形成。与 c-Src 进一步相反，Lyn 缺乏不会影响成熟细胞的活性。 Lyn-/- 小鼠响应 RANKL，在体内经历加速的破骨细胞生成和骨质流失，反映了体外破骨细胞发育的增加。从机制上讲，Lyn 与 NF-kappa B (RANK) 受体激活剂、酪氨酸磷酸酶 SHP-1 和接头蛋白 Grb2 相关结合物 2 (Gab2) 形成复合物。暴露于 RANKL 后，Lyn-/- 破骨细胞中的 Gab2 磷酸化、JNK 和 NF-κ B 激活均增强，这些都是破骨细胞发育中的关键事件。因此，我们确定 Lyn 调节破骨细胞的形成，并以与 c-Src 相反的方式进行。我们的研究结果最务实的方面是，在破骨细胞的背景下，成功地治疗性抑制 c-Src 将需要其严格的靶向性。
c-Src kinase is a rate-limiting activator of osteoclast (OC) function and Src inhibitors are therefore candidate antiosteoporosis drugs. By affecting alpha nu beta 3 and macrophage-colony stimulating factor (M-CSF)-induced signaling, c-Src is central to osteoclast activity, but not differentiation. We find Lyn, another member of Src family kinases (SFK) is, in contrast, a negative regulator of osteoclastic bone resorption. The absence of Lyn enhances receptor activator of NF-kappa B ligand (RANKL)-mediated differentiation of osteoclast precursors without affecting proliferation and survival, while its overexpression decreases osteoclast formation. In further contrast to c-Src, Lyn deficiency does not impact the activity of the mature cell. Reflecting increased osteoclast development in vitro, Lyn-/- mice undergo accelerated osteoclastogenesis and bone loss, in vivo, in response to RANKL. Mechanistically, Lyn forms a complex with receptor activator of NF-kappa B (RANK), the tyrosine phosphatase, SHP-1, and the adapter protein, Grb2-associated binder 2 (Gab2). Upon RANKL exposure, Gab2 phosphorylation, JNK, and NF-kappa B activation are enhanced in Lyn-/- osteoclasts, all critical events in osteoclast development. We therefore establish that Lyn regulates osteoclast formation and does it in a manner antithetical to that of c-Src. The most pragmatic aspect of our findings is that successful therapeutic inhibition of c-Src, in the context of the osteoclast, will require its stringent targeting.