Roles of cathelicidin-related antimicrobial peptide in murine osteoclastogenesis
Roles of cathelicidin-related antimicrobial peptide in murine osteoclastogenesis
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DOI：
10.1111/imm.12146
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发表时间：
2013-11-01
期刊：
影响因子：
6.4
通讯作者：
Udagawa, Nobuyuki
中科院分区：
文献类型：
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作者：
Horibe, Kanji;Nakamichi, Yuko;Udagawa, Nobuyuki
Cathelicidin相关的抗菌肽（CRAMP）不仅可以杀死细菌，而且可以与脂多糖（LPS）结合以中和其活性。CRAMP在骨髓中高度表达，并且据报道其表达被炎症和感染刺激上调。在这里，我们研究了CRAMP在小鼠破骨细胞生成中的作用。破骨细胞在成骨细胞和骨髓细胞的共培养物中形成，以响应1，25-二羟维生素D-3 [1，25（OH）（2）D-3]、前列腺素E-2（PGE（2））和Toll样受体（TLR）配体（例如LPS和鞭毛蛋白）通过诱导成骨细胞中核因子B配体受体激活剂（RANKL）的表达。CRAMP抑制LPS和鞭毛蛋白处理的共培养物中的破骨细胞生成，但不抑制1，25（OH）（2）D-3或PGE处理的共培养物中的破骨细胞生成。尽管骨髓巨噬细胞（BMM）高度表达甲酰肽受体2（CRAMP的一种受体），但在RANKL处理的BMM培养物中，CRAMP对破骨细胞生成无抑制作用。CRAMP抑制了LPS和鞭毛蛋白诱导的成骨细胞RANKL表达和肿瘤坏死因子（TNF-α）表达，表明CRAMP中和了LPS和鞭毛蛋白的作用。LPS和鞭毛蛋白可促进成骨细胞CRAMP mRNA的表达。细胞外添加的CRAMP抑制LPS和鞭毛蛋白诱导的CRAMP表达。这些结果提示，成骨细胞释放的CRAMP通过反馈调节抑制LPS和鞭毛蛋白促进的CRAMP的产生。尽管CRAMP本身对小鼠破骨细胞生成没有影响，但我们认为CRAMP在细菌感染诱导的骨吸收中是成骨细胞源性保护剂。
Cathelicidin-related antimicrobial peptide (CRAMP) not only kills bacteria but also binds to lipopolysaccharide (LPS) to neutralize its activity. CRAMP is highly expressed in bone marrow and its expression is reported to be up-regulated by inflammatory and infectious stimuli. Here, we examined the role of CRAMP in murine osteoclastogenesis. Osteoclasts were formed in co-cultures of osteoblasts and bone marrow cells in response to 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3], prostaglandin E-2 (PGE(2)), and Toll-like receptor (TLR) ligands such as LPS and flagellin through the induction of receptor activator of nuclear factor-B ligand (RANKL) expression in osteoblasts. CRAMP inhibited the osteoclastogenesis in co-cultures treated with LPS and flagellin, but not in those treated with 1,25(OH)(2)D-3 or PGE(2). Although bone marrow macrophages (BMMs) highly expressed formyl peptide receptor 2 (a receptor of CRAMP), CRAMP showed no inhibitory effect on osteoclastogenesis in BMM cultures treated with RANKL. CRAMP suppressed both LPS- and flagellin-induced RANKL expression in osteoblasts and tumour necrosis factor- (TNF-) expression in BMMs, suggesting that CRAMP neutralizes the actions of LPS and flagellin. LPS and flagellin enhanced the expression of CRAMP mRNA in osteoblasts. Extracellularly added CRAMP suppressed LPS- and flagellin-induced CRAMP expression. These results suggest that the production of CRAMP promoted by LPS and flagellin is inhibited by CRAMP released by osteoblasts through a feedback regulation. Even though CRAMP itself has no effect on osteoclastogenesis in mice, we propose that CRAMP is an osteoblast-derived protector in bacterial infection-induced osteoclastic bone resorption.