Calreticulin inhibits inflammation-induced osteoclastogenesis and bone resorption.
Calreticulin inhibits inflammation-induced osteoclastogenesis and bone resorption.
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DOI：
10.1002/jor.23587
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Lee FY
中科院分区：
文献类型：
--
作者：
Fischer CR;Mikami M;Minematsu H;Nizami S;Goo Lee H;Stamer D;Patel N;Yu Soung D;Back JH;Song L;Drissi H;Lee FY
破骨细胞在骨重建和病理性溶骨性疾病（例如炎症、感染、骨植入物松动、类风湿性关节炎、转移性骨癌和病理性骨折）中发挥关键作用。破骨细胞是由单核细胞响应 NF-κB 配体 (RANKL) 和巨噬细胞集落刺激因子 1 (M-CSF) 受体激活剂的融合而形成的。钙网蛋白 (CRT) 是一种众所周知的细胞内蛋白，作为钙结合伴侣，当其重组形式应用于体外破骨细胞前体或体内外部骨炎症部位时，具有出乎意料的强大抗破骨细胞生成作用。外部应用的钙网蛋白被内化到细胞内。在体外用 RANKL 处理的破骨细胞前体细胞中，它抑制关键的促破骨细胞转录因子，例如 c-Fos 和活化 T 细胞核因子、细胞质 1 (NFATc1)。重组人钙网蛋白 (rhCRT) 在体内抑制小鼠颅骨中脂多糖 (LPS) 诱导的炎症破骨细胞生成。组织蛋白酶 K 分子成像证实，当在体内 LPS 应用部位应用 rhCalreticulin 时，组织蛋白酶 K 活性降低。细胞内蛋白或其衍生物的重组形式可以作为新型细胞外治疗剂。我们预计我们的发现将成为揭示许多器官的不同细胞类型中其他细胞内蛋白质隐藏的细胞外功能的起点，以获得新的治疗机会。
Osteoclasts play key roles in bone remodeling and pathologic osteolytic disorders such as inflammation, infection, bone implant loosening, rheumatoid arthritis, metastatic bone cancers, and pathological fractures. Osteoclasts are formed by the fusion of monocytes in response to receptor activators of NF-κB-ligand (RANKL) and macrophage colony stimulating factor 1 (M-CSF). Calreticulin (CRT), a commonly known intracellular protein as a calcium-binding chaperone, has an unexpectedly robust anti-osteoclastogenic effect when its recombinant form is applied to osteoclast precursors in vitro or at the site of bone inflammation externally in vivo. Externally applied Calreticulin was internalized inside the cells. It inhibited key pro-osteoclastogenic transcription factors such as c-Fos and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) in osteoclast precursor cells that were treated with RANKL in vitro. Recombinant human Calreticulin (rhCRT) inhibited lipopolysaccharide (LPS)-induced inflammatory osteoclastogenesis in the mouse calvarial bone in vivo. Cathepsin K molecular imaging verified decreased Cathepsin K activity when rhCalreticulin was applied at the site of LPS application in vivo. Recombinant forms of intracellular proteins or their derivatives may act as novel extracellular therapeutic agents. We anticipate our findings to be a starting point in unraveling hidden extracellular functions of other intracellular proteins in different cell types of many organs for new therapeutic opportunities.
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发表时间：
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影响因子：
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