Impaired skeletal development in interleukin-6-transgenic mice

A model for the impact of chronic inflammation on the growing skeletal system

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

Research output: Contribution to journalArticle

173 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3551-3563
Number of pages13
JournalArthritis and Rheumatism
Volume54
Issue number11
DOIs
Publication statusPublished - Nov 2006

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Transgenic Mice
Interleukin-6
Osteogenesis
Inflammation
Osteoblasts
Growth Plate
Bone and Bones
Minerals
Growth Disorders
X-Ray Microtomography
Metabolic Bone Diseases
Osteoclasts
Bone Resorption
Growth
Child Development
Reverse Transcriptase Polymerase Chain Reaction
Skull
Skeleton
Histology
Chronic Disease

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

Impaired skeletal development in interleukin-6-transgenic mice : A model for the impact of chronic inflammation on the growing skeletal system. / De Benedetti, Fabrizio; Rucci, Nadia; Del Fattore, Andrea; Peruzzi, Barbara; Paro, Rita; Longo, Maurizio; Vivarelli, Marina; Muratori, Flaminia; Berni, Silvia; Ballanti, Paola; Ferrari, Serge; Teti, Anna.

In: Arthritis and Rheumatism, Vol. 54, No. 11, 11.2006, p. 3551-3563.

Research output: Contribution to journalArticle

De Benedetti, Fabrizio ; Rucci, Nadia ; Del Fattore, Andrea ; Peruzzi, Barbara ; Paro, Rita ; Longo, Maurizio ; Vivarelli, Marina ; Muratori, Flaminia ; Berni, Silvia ; Ballanti, Paola ; Ferrari, Serge ; Teti, Anna. / Impaired skeletal development in interleukin-6-transgenic mice : A model for the impact of chronic inflammation on the growing skeletal system. In: Arthritis and Rheumatism. 2006 ; Vol. 54, No. 11. pp. 3551-3563.
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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.",
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T1 - Impaired skeletal development in interleukin-6-transgenic mice

T2 - A model for the impact of chronic inflammation on the growing skeletal system

AU - De Benedetti, Fabrizio

AU - Rucci, Nadia

AU - Del Fattore, Andrea

AU - Peruzzi, Barbara

AU - Paro, Rita

AU - Longo, Maurizio

AU - Vivarelli, Marina

AU - Muratori, Flaminia

AU - Berni, Silvia

AU - Ballanti, Paola

AU - Ferrari, Serge

AU - Teti, Anna

PY - 2006/11

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N2 - 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.

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