IL-1是一个炎症有关的细胞因子。在各种病理条件下，IL-1被发现与骨质疏松有关。研究表明，其促进了破骨细胞的形成、生长以及功能发挥。最近，美国阿拉巴马大学Suzanne M. Michalek等人发现，单独的IL-1就可以有效的延长破骨细胞的生存，同时激活破骨细胞的功能，而且IL-1调节破骨细胞生成需要NF-κB的受体活化剂的帮助。相关论文发表在3月13日的美国《生化周刊》（JBC）上。
一直以来，依赖RANKL的IL-1调节破骨细胞生成的分子基础还未可知。本次研究表明：虽然IL-1不能激活破骨细胞基因编码的基质金属蛋白酶9（MMP9），组织酶K(Ctsk)，抗酒石酸磷酸酶(Car2)在骨髓巨噬细胞(BMMs)中的表达，RANKL可以致使这些破骨细胞基因应答于IL-1。
实验进一步证明，单独的IL-1不能够引起NFATc1（一中对破骨细胞生成的主导性转录调节因子）的表达，但是，如果有一定水平的RANKL或者RANKL预处理物的话，IL-1在BMMs中可以上调NFATc1的表达。
最后，本次实验发现，一种已知的，在IL-1RI 信号通路中的关键部件--MyD88，通过其上调破骨细胞标记以及NFATc1基因的表达，在IL-1调节的破骨细胞生成中起着至关重要的作用。
这项研究发现了IL-1调节破骨细胞生成的新奇机制，支持了IVVY模体作为治疗炎症骨骼流失的最具治疗潜力的位点这一观点。（生物谷Bioon.com）
doi: 10.1074/jbc.M111.296228
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Molecular basis of the requirement of RANK signaling for interleukin-1 (IL-1)-mediated osteoclastogenesis
Joel Jules, Ping Zhang, Jason W Ashley, Shi Wei, Zhenqi Shi, Jiangzhong Liu, Suzanne M. Michalek and Xu Feng.
Interleukin-1 (IL-1), a proinflammatory cytokine, is implicated in bone loss in various pathological conditions by promoting osteoclast formation, survival and function. Whereas IL-1 alone can sufficiently prolong osteoclast survival and activate osteoclast function, IL-1-mediated osteoclastogenesis requires the receptor activator of NF-κB (RANK) ligand (RANKL).However, the molecular basis of the dependence of IL-1-mediated osteoclastogenesis on RANKL is not fully understood. Here we show that while IL-1 cannot activate the expression of the osteoclast genes encoding matrix metalloproteinase 9 (MMP9), cathepsin K (Ctsk), tartrate-resistant acid phosphatase (TRAP) and carbonic anhydrase II (Car2) in bone marrow macrophages (BMMs), RANKL renders these osteoclast genes responsive to IL-1.We further demonstrate that IL-1 alone fails to induce the expression of NFATc1, a master transcriptional regulator of osteoclastogenesis, in BMMs but can up-regulate its expression in the presence of permissive levels of RANKL or with RANKL pretreatment. The RANK IVVY motif, which has been previously shown to commit BMMs to the osteoclast lineage in RANKL- and tumor necrosis factor-α (TNF)-mediated osteoclastogenesis, also plays a crucial role in IL-1-mediated osteoclastogenesis by changing the four osteoclast marker and NFATc1 genes to an IL-1-inducible state.Finally, we show that MyD88, a known critical component of the IL-1RI signaling pathway, plays a crucial role in IL-1-mediated osteoclastogenesis from RANKL-primed BMMs by up-regulating the expression of the osteoclast marker and NFATc1 genes. These studies reveal a novel mechanism of IL-1-mediated osteoclastogenesis and support the promising potential of the IVVY motif to serve as a therapeutic target for inflammatory bone loss.
