IL-1是一個(gè)炎癥有關(guān)的細(xì)胞因子,。在各種病理?xiàng)l件下，IL-1被發(fā)現(xiàn)與骨質(zhì)疏松有關(guān),。研究表明,，其促進(jìn)了破骨細(xì)胞的形成,、生長(zhǎng)以及功能發(fā)揮。最近,，美國(guó)阿拉巴馬大學(xué)Suzanne M. Michalek等人發(fā)現(xiàn),，單獨(dú)的IL-1就可以有效的延長(zhǎng)破骨細(xì)胞的生存，同時(shí)激活破骨細(xì)胞的功能,，而且IL-1調(diào)節(jié)破骨細(xì)胞生成需要NF-κB的受體活化劑的幫助,。相關(guān)論文發(fā)表在3月13日的美國(guó)《生化周刊》（JBC）上。
一直以來(lái),，依賴RANKL的IL-1調(diào)節(jié)破骨細(xì)胞生成的分子基礎(chǔ)還未可知,。本次研究表明：雖然IL-1不能激活破骨細(xì)胞基因編碼的基質(zhì)金屬蛋白酶9（MMP9），組織酶K(Ctsk),，抗酒石酸磷酸酶(Car2)在骨髓巨噬細(xì)胞(BMMs)中的表達(dá),，RANKL可以致使這些破骨細(xì)胞基因應(yīng)答于IL-1。
實(shí)驗(yàn)進(jìn)一步證明,，單獨(dú)的IL-1不能夠引起NFATc1（一中對(duì)破骨細(xì)胞生成的主導(dǎo)性轉(zhuǎn)錄調(diào)節(jié)因子）的表達(dá),，但是，如果有一定水平的RANKL或者RANKL預(yù)處理物的話,，IL-1在BMMs中可以上調(diào)NFATc1的表達(dá),。
最后，本次實(shí)驗(yàn)發(fā)現(xiàn),，一種已知的,，在IL-1RI 信號(hào)通路中的關(guān)鍵部件--MyD88，通過(guò)其上調(diào)破骨細(xì)胞標(biāo)記以及NFATc1基因的表達(dá),，在IL-1調(diào)節(jié)的破骨細(xì)胞生成中起著至關(guān)重要的作用,。
這項(xiàng)研究發(fā)現(xiàn)了IL-1調(diào)節(jié)破骨細(xì)胞生成的新奇機(jī)制，支持了IVVY模體作為治療炎癥骨骼流失的最具治療潛力的位點(diǎn)這一觀點(diǎn),。（生物谷Bioon.com）
doi: 10.1074/jbc.M111.296228
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PMID:
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.
