Direct inhibition of human RANK+ osteoclast precursors identifies a homeostatic function of IL-1beta.
Direct inhibition of human RANK+ osteoclast precursors identifies a homeostatic function of IL-1beta.
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DOI：
10.4049/jimmunol.1001591
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发表时间：
2010-11-15
期刊：
影响因子：
--
通讯作者：
Ji JD
中科院分区：
文献类型：
--
作者：
Lee B;Kim TH;Jun JB;Yoo DH;Woo JH;Choi SJ;Lee YH;Song GG;Sohn J;Park-Min KH;Ivashkiv LB;Ji JD
IL-1β是炎性环境（如类风湿性关节炎（RA））中骨吸收的关键介质。IL-1β通过诱导基质细胞上RANKL表达并与RANKL协同促进破骨细胞分化的后期阶段来促进破骨细胞生成。由于IL-1 R与TLR共享胞质Toll-IL-1 R结构域和共同的细胞内信号传导分子，可以直接抑制人破骨细胞分化的早期步骤，我们测试了IL-1β是否也对原代人外周血单核细胞和RA滑膜巨噬细胞中的破骨细胞生成具有抑制特性。通过TRAP+多核细胞的生成评估，在RANKL之前或与RANKL一起早期添加IL-1β可强烈抑制人破骨细胞生成。IL-1β直接作用于人破骨细胞前体细胞（OCP），强烈抑制RANK、髓样细胞2受体上表达的共刺激触发受体和对传递RANK诱导信号很重要的B细胞接头衔接子的表达。因此，IL-1β使早期人类OCP对RANK刺激不敏感。使用RA滑膜巨噬细胞观察到IL-1β的类似抑制作用。RANK抑制的一种机制是IL-1β诱导RANK表达所需的M-CSF受体c-Fms的蛋白水解脱落。这些结果确定了IL-1β在抑制早期OCP中的稳态功能，这与其在促进破骨细胞分化的后期阶段中的公认作用形成对比。因此，在炎性疾病如RA中IL-1驱动的骨破坏的速率可以通过其对早期OCP的直接抑制作用来抑制，以限制炎性骨质溶解的程度。
IL-1β is a key mediator of bone resorption in inflammatory settings, such as rheumatoid arthritis (RA). IL-1β promotes osteoclastogenesis by inducing RANKL expression on stromal cells and synergizing with RANKL to promote later stages of osteoclast differentiation. Because IL-1Rs share a cytosolic Toll–IL-1R domain and common intracellular signaling molecules with TLRs that can directly inhibit early steps of human osteoclast differentiation, we tested whether IL-1β also has suppressive properties on osteoclastogenesis in primary human peripheral blood monocytes and RA synovial macrophages. Early addition of IL-1β, prior to or together with RANKL, strongly inhibited human osteoclastogenesis as assessed by generation of TRAP+ multinucleated cells. IL-1β acted directly on human osteoclast precursors (OCPs) to strongly suppress expression of RANK, of the costimulatory triggering receptor expressed on myeloid cells 2 receptor, and of the B cell linker adaptor important for transmitting RANK-induced signals. Thus, IL-1β rendered early-stage human OCPs refractory to RANK stimulation. Similar inhibitory effects of IL-1β were observed using RA synovial macrophages. One mechanism of RANK inhibition was IL-1β–induced proteolytic shedding of the M-CSF receptor c-Fms that is required for RANK expression. These results identify a homeostatic function of IL-1β in suppressing early OCPs that contrasts with its well-established role in promoting later stages of osteoclast differentiation. Thus, the rate of IL-1–driven bone destruction in inflammatory diseases, such as RA, can be restrained by its direct inhibitory effects on early OCPs to limit the extent of inflammatory osteolysis.
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DOI：
10.1084/jem.191.2.313
发表时间：
2000-01-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Horai R;Saijo S;Tanioka H;Nakae S;Sudo K;Okahara A;Ikuse T;Asano M;Iwakura Y
通讯作者：
Iwakura Y
DOI：
10.1084/jem.190.12.1741
发表时间：
1999-12-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Arai F;Miyamoto T;Ohneda O;Inada T;Sudo T;Brasel K;Miyata T;Anderson DM;Suda T
通讯作者：
Suda T
DOI：
10.4049/jimmunol.0804165
发表时间：
2009-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Park-Min KH;Ji JD;Antoniv T;Reid AC;Silver RB;Humphrey MB;Nakamura M;Ivashkiv LB
通讯作者：
Ivashkiv LB
DOI：
10.1073/pnas.0502562102
发表时间：
2005-09-06
影响因子：
11.1
作者：
Bajayo, A;Goshen, I;Bab, I
通讯作者：
Bab, I
影响因子：
64.8
作者：
GOWEN, M;WOOD, DD;RUSSELL, RGG
通讯作者：
RUSSELL, RGG