Impaired skeletal development in interleukin-6-transgenic mice - A model for the impact of chronic inflammation on the growing skeletal system
Impaired skeletal development in interleukin-6-transgenic mice - A model for the impact of chronic inflammation on the growing skeletal system
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DOI：
10.1002/art.22175
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发表时间：
2006-11-01
影响因子：
--
通讯作者：
Teti, Anna
中科院分区：
文献类型：
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作者：
De Benedetti, Fabrizio;Rucci, Nadia;Teti, Anna
Objective.为了确定慢性炎症对儿童骨骼发育的影响（骨丢失、骨峰值增加缺陷、生长迟缓）的介质，我们评估了慢性白细胞介素-6（IL-6）过表达对生长中的青春期前小鼠骨骼的影响。我们研究了IL-6转基因小鼠，这些小鼠自出生以来就具有高循环IL-6水平。骨小梁和皮质骨结构进行了分析，显微计算机断层扫描。通过组织学/组织形态计量学研究骨骺骨化、生长板和颅骨。体外研究破骨细胞生成、成骨细胞功能/分化以及IL-6对骨细胞的影响。逆转录聚合酶链反应检测成骨细胞基因表达。采用在体双荧光标记法动态评价骨皮质中的矿物质沉积率。在青春期前IL-6转基因小鼠中，我们观察到骨质减少，皮质骨和骨小梁微结构发生严重改变，骨形成与骨吸收脱钩，成骨细胞减少，破骨细胞数量和活性增加。破骨细胞生成增加和成骨细胞活性降低，继发于前体细胞增殖和成骨细胞功能降低。IL-6转基因小鼠也表现出生长板和骨骺骨化中心发育受损。膜内骨化和软骨内骨化以及矿物质沉积率明显受到影响，表明存在骨化缺陷。单独的IL-6的慢性过度表达诱导骨骼表型，其与在患有慢性炎症性疾病的儿童中观察到的生长和骨骼异常非常相似，指出IL-6是慢性炎症对出生后骨骼发育的影响的关键介质。我们假设IL-6修饰药物可以减少骨骼缺陷并预防与这些疾病相关的生长迟缓。
Objective. To identify the mediator responsible for the impact of chronic inflammation on skeletal development in children (bone loss, defective peak bone mass accrual, stunted growth), we evaluated the effects of chronic interleukin-6 (IL-6) overexpression on the skeletons of growing prepubertal mice.Methods. We studied IL-6-transgenic mice that had high circulating IL-6 levels since birth. Trabecular and cortical bone structure were analyzed by microcomputed tomography. Epiphyseal ossification, growth plates, and calvariae were studied by histology/histomorphometry. Osteoclastogenesis, osteoblast function/differentiation, and the effects of IL-6 on bone cells were studied in vitro. Osteoblast gene expression was evaluated by reverse transcriptase-polymerase chain reaction. The mineral apposition rate was evaluated dynamically in cortical bone by in vivo double fluorescence labeling.Results. In prepubertal IL-6-transgenic mice, we observed osteopenia, with severe alterations in cortical and trabecular bone microarchitecture, as well as uncoupling of bone formation from resorption, with decreased osteoblast and increased osteoclast number and activity. Increased osteoclastogenesis and reduced osteoblast activity, secondary to decreased precursor proliferation and osteoblast function, were present. IL-6-transgenic mice also showed impaired development of growth plates and epiphyseal ossification centers. Intramembranous and endochondral ossification and the mineral apposition rate were markedly affected, showing the presence of defective ossification.Conclusion. Chronic overexpression of IL-6 alone induces a skeletal phenotype closely resembling growth and skeletal abnormalities observed in children with chronic inflammatory diseases, pointing to IL-6 as a pivotal mediator of the impact of chronic inflammation on postnatal skeletal development. We hypothesize that IL-6-modifying drugs may reduce skeletal defects and prevent the growth retardation associated with these diseases.