Impaired skeletal development in interleukin-6–transgenic mice: A model for the impact of chronic inflammation on the growing skeletal system
✍ Scribed by Fabrizio De Benedetti; Nadia Rucci; Andrea Del Fattore; Barbara Peruzzi; Rita Paro; Maurizio Longo; Marina Vivarelli; Flaminia Muratori; Silvia Berni; Paola Ballanti; Serge Ferrari; Anna Teti
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- English
- Weight
- 933 KB
- Volume
- 54
- Category
- Article
- ISSN
- 0004-3591
No coin nor oath required. For personal study only.
✦ Synopsis
Abstract
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.