Cytokine regulation and the signaling mechanism of osteoclast inhibitory peptide-1 (OIP-1/hSca) to inhibit osteoclast formation
Cytokine regulation and the signaling mechanism of osteoclast inhibitory peptide-1 (OIP-1/hSca) to inhibit osteoclast formation
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DOI：
10.1359/jbmr.2003.18.3.458
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发表时间：
2003-03-01
影响因子：
6.2
通讯作者：
Reddy, SV
中科院分区：
文献类型：
--
作者：
Koide, M;Maeda, H;Reddy, SV
破骨细胞（OCL）是主要的骨吸收细胞。OCL的形成和活性受骨微环境中产生的局部因素调节。我们最近发现OCL抑制肽-1（OIP-1/hSca）是一种新的OCL形成和骨吸收的抑制剂。OIP-1是与小鼠造血蛋白Ly-6家族相关的糖基磷脂酰肌醇（GPI）连接的膜蛋白（16 kDa）。OIP-1 mRNA在人OCL前体细胞、粒细胞-巨噬细胞集落形成单位（GM-CFU）、骨髓细胞和成骨细胞中表达。我们使用周期依赖性逆转录酶-聚合酶链反应（RT-PCR）分析，进一步证明干扰素-γ（IFN-γ）强烈增强骨髓细胞和GM-CFU中OIP-1/hSca mRNA的表达。同样，白细胞介素（IL）-1 β也增强了GM-CFU中OIP-1 mRNA的表达。为了确定OIP-1在IFN-γ抑制OCL形成中的参与，我们测试了对OIP-1 c-肽特异性的中和抗体抑制IFN-γ对小鼠巨噬细胞RAW 264.7细胞的OCL样细胞分化的作用的能力。抗OIP-1 c肽特异性抗体部分中和了IFN-γ对OCL分化的抑制作用。此外，OIP-1抑制RAW 264.7细胞中的磷酸-c-Jun（p-c-jun）激酶活性。然而，OIP-1/hSca不影响这些细胞中的NF-κ B活化。Western印迹分析进一步证明OIP-1显著降低RAW 264.7细胞中TNF受体相关因子2（TRAF-2）的表达。然而，OIP-1对这些细胞中TRAF-6的表达没有影响。这些数据表明IFN-γ增强OCL前体GM-CFU中的OIP-1/hSca表达，并且OIP-1通过抑制TRAF-2和p-c-Jun激酶活性抑制OCL形成。
The osteoclast (OCL) is the primary bone resorbing cell. OCL formation and activity is regulated by local factors produced in the bone microenvironment. We recently identified OCL inhibitory peptide-1 (OIP-1/hSca) as a novel inhibitor of OCL formation and bone resorption that is produced by OCLs. OIP-1 is a glycosylphosphatidyl-inositol (GPI)-linked membrane protein (16 kDa) related to the mouse Ly-6 family of hematopoietic proteins. OIP-1 mRNA is expressed in human OCL precursors, granulocyte-macrophage colony-forming unit (GM-CFU), bone marrow cells, and osteoblast cells. We used cycle-dependent reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, which further demonstrated that interferon-gamma (IFN-gamma) strongly enhanced OIP-1/hSca mRNA expression in bone marrow cells and GM-CFU. Similarly, interleukin (IL)-1beta also enhanced OIP-1 mRNA expression in GM-CFU. To determine the participation of OIP-1 in IFN-gamma inhibition of OCL formation, we tested the capacity of a neutralizing antibody specific to OIP-1 c-peptide to inhibit IFN-gamma's effects on OCL-like cell differentiation of mouse macrophages, RAW 264.7 cells. Anti-OIP-1 c-peptide specific antibody partially neutralized IFN-gamma inhibition of OCL differentiation. Furthermore, OIP-1 inhibited phospho-c-Jun (p-c-jun) kinase activity in RAW 264.7 cells. However, OIP-1/hSca did not affect NF-kappaB activation in these cells. Western blot analysis further demonstrated that OIP-1 significantly decreased TNF receptor associated factor 2 (TRAF-2) expression in RAW 264.7 cells. However, OIP-1 had no effect on TRAF-6 expression in these cells. These data show that IFN-gamma enhances OIP-1/hSca expression in OCL precursors, GM-CFU, and that OIP-1 inhibits OCL formation through suppression of TRAF-2 and p-c-Jun kinase activity.