Ah Kioon Marie-Dominique, Asensio Carine, Ea Hang-Korng, Velard Frédéric, Uzan Benjamin, Rullé Sandrine, Bazille Céline, Marty Caroline, Falgarone Géraldine, Nguyen Christelle, Collet Corinne, Launay Jean-Marie, Cohen-Solal Martine, Lioté Frédéric
INSERM, UMR-S 606, Hôpital Lariboisière, AP-HP, Université Paris Diderot, Paris, France.
Arthritis Rheum. 2012 Apr;64(4):1069-81. doi: 10.1002/art.33426. Epub 2011 Oct 17.
Adrenomedullin(22-52) is a truncated peptide derived from adrenomedullin, a growth factor with antiapoptotic and immunoregulatory properties. It can act as an agonist or an antagonist depending on cell type. Its in vivo effects are unknown, but adrenomedullin(22-52) could possess immunomodulatory properties. This study was undertaken to evaluate the effect of adrenomedullin(22-52) in a mouse model of arthritis.
DBA/1 mice with collagen-induced arthritis (CIA) were treated with 1.2 μg/gm adrenomedullin(22-52) , adrenomedullin, or saline at arthritis onset. Bone mineral density was measured at the beginning of the experiment and when mice were killed. Mouse joints were processed for histologic analysis and protein studies, and spleens were examined for Treg cell expression. Cytokine expression was studied in mouse joint tissue and serum.
In mice with CIA, adrenomedullin and adrenomedullin(22-52) reduced clinical and histologic arthritis scores and shifted the pattern of articular and systemic cytokine expression from Th1 to Th2, as compared to untreated mice with CIA (controls). Tumor necrosis factor α, interleukin-6 (IL-6), and IL-17A levels were significantly decreased in the joints of mice with CIA treated with adrenomedullin or adrenomedullin(22-52) as compared to controls, whereas IL-4 and IL-10 levels were increased. Adrenomedullin(22-52) was more effective than adrenomedullin in modulating cytokine content and enhanced Treg cell function without changing Treg cell expression compared to controls. Adrenomedullin receptor binding and transcriptional adrenomedullin receptor expression were markedly increased in joints from controls, whereas adrenomedullin receptor binding was considerably decreased in treated animals. Mice with CIA treated with adrenomedullin or adrenomedullin(22-52) had considerably fewer apoptotic chondrocytes and diminished cartilage degradation. Adrenomedullin(22-52) completely prevented systemic bone loss by preserving osteoblastic activity, but without changes in osteoclastic activity.
Our findings indicate that adrenomedullin(22-52) , which has no vasoactive or tumor-inducing effects, is a potent antiinflammatory and bone-protective agent in this arthritis model.
肾上腺髓质素（22 - 52）是一种源自肾上腺髓质素的截短肽，肾上腺髓质素是一种具有抗凋亡和免疫调节特性的生长因子。它可根据细胞类型充当激动剂或拮抗剂。其体内作用尚不清楚，但肾上腺髓质素（22 - 52）可能具有免疫调节特性。本研究旨在评估肾上腺髓质素（22 - 52）在小鼠关节炎模型中的作用。
胶原诱导性关节炎（CIA）的DBA/1小鼠在关节炎发作时用1.2μg/g体重的肾上腺髓质素（22 - 52）、肾上腺髓质素或生理盐水进行治疗。在实验开始时以及小鼠处死时测量骨密度。对小鼠关节进行组织学分析和蛋白质研究，并检查脾脏中调节性T细胞（Treg）的表达。研究小鼠关节组织和血清中的细胞因子表达。
与未治疗的CIA小鼠（对照组）相比，在CIA小鼠中，肾上腺髓质素和肾上腺髓质素（22 - 52）降低了临床和组织学关节炎评分，并使关节和全身细胞因子表达模式从Th1转变为Th2。与对照组相比，用肾上腺髓质素或肾上腺髓质素（22 - 52）治疗的CIA小鼠关节中的肿瘤坏死因子α、白细胞介素 - 6（IL - 6）和IL - 17A水平显著降低，而IL - 4和IL - 10水平升高。与对照组相比，肾上腺髓质素（22 - 52）在调节细胞因子含量方面比肾上腺髓质素更有效，并且在不改变Treg细胞表达的情况下增强了Treg细胞功能。对照组关节中的肾上腺髓质素受体结合和转录性肾上腺髓质素受体表达明显增加，而在治疗动物中肾上腺髓质素受体结合显著降低。用肾上腺髓质素或肾上腺髓质素（22 - 52）治疗的CIA小鼠凋亡软骨细胞明显减少，软骨降解减轻。肾上腺髓质素（22 - 52）通过保留成骨细胞活性完全防止了全身性骨质流失，但破骨细胞活性没有变化。
我们的研究结果表明，肾上腺髓质素（22 - 52）无血管活性或肿瘤诱导作用，在该关节炎模型中是一种有效的抗炎和骨保护剂。
