Impaired skeletal development in interleukin‐6–transgenic mice: A model for the impact of chronic inflammation on the growing skeletal system

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.

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

“…It is interesting to note that, in mice overexpressing human IL-6, in which the transgene is not modulated but is able to induce endogenous (mouse) IL-6 upregulation, c-Src inhibitor was again able to impair the expression of this latter in the tibia. Moreover, c-Src inhibition had a strong anabolic effect on the bone of IL-6 TG mice, in which osteoblasts are negatively affected by IL-6 overexpression 13 .…”

“…4a). Interestingly, while tumour-necrosis factor-α was insensitive to the treatment with CGP76030, IL-1β, which is known to be induced by IL-6 itself 13 , was subjected to similar downregulation by CGP76030 as IL-6.…”

“…In our previous work, we characterized the bone phenotype of a prepubertal mouse model, in which IL-6 is expressed at a high level in the bloodstream 13 , demonstrating stunted skeletal growth and osteopenia, with accelerated bone resorption, reduced bone formation and defective ossification. Enhanced bone resorption was due to increased osteoclastogenesis, while reduced osteoblast activity was induced by a mechanism affecting precursor proliferation and mature osteoblast function 13 .…”

“…Enhanced bone resorption was due to increased osteoclastogenesis, while reduced osteoblast activity was induced by a mechanism affecting precursor proliferation and mature osteoblast function 13 .…”

IKKβ in postnatal perichondrium remotely controls endochondral ossification of the growth plate through downregulation of MCP-5

“…Then, we examined the expression of genes encoding cytokines that were reported to affect endochondral ossification. 17,[29][30][31] As shown in Figure 6c, among the cytokines examined, Il-1β and Mcp-5 displayed big differences between Ikkβ Prx1KO and control mice. Although IL-1β is reported to inhibit the differentiation of chondrocytes, 29,32 it was downregulated in the perichondrium of Ikkβ Prx1KO mice and thus fails to explain the phenotype.…”