ARTHRITIS & RHEUMATISM Vol. 54, No. 11, November 2006, pp 3551–3563 DOI 10.1002/art.22175 © 2006, American College of Rheumatology Impaired Skeletal Development in Interleukin-6–Transgenic Mice A Model for the Impact of Chronic Inflammation on the Growing Skeletal System Fabrizio De Benedetti, 1 Nadia Rucci, 2 Andrea Del Fattore, 2 Barbara Peruzzi, 2 Rita Paro, 2 Maurizio Longo, 2 Marina Vivarelli, 1 Flaminia Muratori, 1 Silvia Berni, 3 Paola Ballanti, 3 Serge Ferrari, 4 and Anna Teti 2 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 micro- computed 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 evalu- ated 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 un- coupling of bone formation from resorption, with de- creased osteoblast and increased osteoclast number and activity. Increased osteoclastogenesis and reduced os- teoblast activity, secondary to decreased precursor pro- liferation and osteoblast function, were present. IL-6– transgenic mice also showed impaired development of growth plates and epiphyseal ossification centers. In- tramembranous and endochondral ossification and the mineral apposition rate were markedly affected, show- ing 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. Children with juvenile idiopathic arthritis (JIA), particularly those with systemic JIA, may present with a decrease in bone mass and an increased risk of fractures. Later in life, they may reach a suboptimal bone mass peak, which is a well-known risk factor for developing osteoporosis (1,2). These children also present with inhibition of somatic growth, associated with retarded skeletal development and delayed epiphyseal ossifica- tion (3,4). Although malnutrition, physical inactivity, and therapies may contribute to these skeletal abnormalities, several lines of evidence indicate that inflammation itself may play a major role. Low bone mass and stunted growth were demonstrated in JIA patients not treated with glucocorticoids and were found to be associated Supported by an IRCCS grant to Ospedale Pediatrico Bam- bino Gesu `. Dr. Teti’s work was supported by the European Commis- sion grant OSTEOGENE (contract LSHM-CT-2003-502941). 1 Fabrizio De Benedetti, MD, Marina Vivarelli, MD, Flaminia Muratori, PhD: Ospedale Pediatrico Bambino Gesu `, Rome, Italy; 2 Nadia Rucci, PhD, Andrea Del Fattore, BSc, Barbara Peruzzi, BSc, Rita Paro, PhD, Maurizio Longo, PhD, Anna Teti, PhD: University of L’Aquila, L’Aquila, Italy; 3 Silvia Berni, BSc, Paola Ballanti, PhD: University La Sapienza, Rome, Italy; 4 Serge Ferrari, MD: Geneva University Hospital, Geneva, Switzerland. Address correspondence and reprint requests to Anna Teti, PhD, Department of Experimental Medicine, University of L’Aquila, Via Vetoio, Coppito 2, 67100 L’Aquila, Italy. E-mail: teti@univaq.it. Submitted for publication October 27, 2005; accepted in revised form July 24, 2006. 3551