Department of Experimental Medicine, University of L'Aquila, Via Vetoio - Coppito 2, L'Aquila 67100, Italy.
Nat Commun. 2012 Jan 17;3:630. doi: 10.1038/ncomms1651.
Interleukin-6 (IL-6) and c-Src impair osteoblast maturation in vitro and in vivo. Given the similar effects of these factors, they are likely to establish a functional loop to maintain osteoblasts in a less mature status. Here we describe a pathway whereby c-Src stimulates IL-6 expression through the STAT3 factor, which, in response to IL-6 induces insulin-like growth factor 5 (IGFBP5), a c-Src activating factor that amplifies this loop only in immature osteoblasts. In contrast, in mature osteoblasts, IGFBP5 is enhanced by Runx2, but is no longer able to stimulate c-Src activation, as this tyrosine kinase at this stage is downregulated. We find that the IGFBP5 produced by osteoblasts stimulates osteoclastogenesis and bone resorption, acting as an osteoblast-osteoclast coupling factor. Finally, we demonstrate that the integrated actions of c-Src, IL-6 and IGFBP5 also have a role in vivo. We conclude that this pathway is relevant for bone metabolism, both in physiological and in pathological conditions.
白细胞介素 6（IL-6）和 c-Src 在体外和体内均可损害成骨细胞的成熟。鉴于这些因素的相似作用，它们可能建立一个功能循环，使成骨细胞保持在不成熟的状态。在这里，我们描述了一条途径，即 c-Src 通过 STAT3 因子刺激 IL-6 的表达，而 IL-6 又会诱导胰岛素样生长因子 5（IGFBP5），一种 c-Src 激活因子，仅在不成熟的成骨细胞中放大该循环。相比之下，在成熟的成骨细胞中，IGFBP5 受 Runx2 增强，但不再能够刺激 c-Src 激活，因为此时这种酪氨酸激酶被下调。我们发现成骨细胞产生的 IGFBP5 刺激破骨细胞生成和骨吸收，充当成骨细胞-破骨细胞偶联因子。最后，我们证明 c-Src、IL-6 和 IGFBP5 的综合作用在体内也具有作用。我们得出结论，该途径与生理和病理条件下的骨代谢都相关。
