Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion.

Abstract

Interleukin‐6 (IL‐6) is a multifunctional cytokine whose circulating levels are under physiological conditions below detection, but whose production is rapidly and strongly induced by several pathological and inflammatory stimuli. IL‐6 has been implicated in a number of cell functions connected to immunity and hematopoiesis. Recently, it has been proposed to act as a stimulator of osteoclast formation and activity, in particular following estrogen depletion. The purpose of this study was to gain additional insights into the role of IL‐6 during development, as well as in physiological and pathological conditions. We report here that IL‐6 deficient mice generated by gene targeting are viable and do not present any evident phenotypic abnormality. However, analysis of bone metabolism revealed a specific bone phenotype. IL‐6 deficient female mice have a normal amount of trabecular bone, but higher rates of bone turnover than control littermates. Estrogen deficiency induced by ovariectomy causes in wild type animals a significant loss of bone mass together with an increase in bone turnover rates. Strikingly, ovariectomy does not induce any change in either bone mass or bone remodeling rates in the IL‐6 deficient mice. These findings indicate that IL‐6 plays an important role in the local regulation of bone turnover and, at least in mice, appears to be essential for the bone loss caused by estrogen deficiency.

Targeting the interleukin‐6 receptor: A new treatment for systemic juvenile idiopathic arthritis?

“…IL-6 has profound effects on bone and can induce osteoclast differentiation and activation in vitro (51). IL-6 Ϫ/Ϫ mice have been shown to be protected from ovariectomyinduced osteoporosis (52). IL-6-transgenic mice, a model reflecting the overproduction of IL-6 present in chronic inflammatory diseases, show decreased numbers and thicknesses of trabeculae in the secondary spongiosa, reduced cortical thickness, and increased osteoclast numbers and surfaces, with biochemical evidence of increased osteoclastic activity (De Benedetti F, et al: unpublished observations).…”

Mouse cathepsin K: cDNA cloning and predominant expression of the gene in osteoclasts, and in some hypertrophying chondrocytes during mouse development

“…Metaphyseal osteopenia has also been discovered in transgenic mice harboring a dominant negative mutation in the cartilage specific type II collagen gene [5]. On the other hand, knockout mutation of the interleukin-6 gene makes mice resistant to ovariectomy-induced osteoporosis [19]. Targeted inactivation of the c-fos and c-src genes inhibits bone resorption and shifts the balance towards bone formation resulting in osteopetrosis [20,21].…”

Interleukin‐6: Structure‐function relationships

“…While IL-6 appears to have little to do with the day-to-day "housekeeping" functions of the body, along with other cytokines it represents an important frontline component of the body's armory against infection or tissue damage (Akira et al, 1993;Nicola, 1994). In vivo studies using IL-6 knockout mice demonstrate that, while IL-6-deficient mice develop normally, they have impaired immune and acute-phase responses (Fattori et al, 1994;Kopf et al, 1994;Poli et al, 1994;Ramsay et al, 1994).…”

“…In accordance with its functional pleiotropy, IL-6 has been implicated in the pathology of many diseases including multiple myeloma (Kawano et al, 1988;Bataille et al, 1989), rheumatoid arthritis ), Castleman's disease , AIDS (Nakajima et al, 1989;Poli et al, 1990), mesangial proliferative glomerulonephritis (Horii et al, 1989), psoriasis (Grossman et al, 1989), Kaposi's sarcoma (Miles et al, 1990), sepsis (Waage et al, 1989), and osteoporosis (Jilka et al, 1992; Poli et al, 1994). Given the association of abnormal IL-6 production and clinical disorders (for reviews see Akira et al, 1993;Hirano, 1994;, there is intense interest in both understanding the biochemical mechanisms controlled by IL-6, and in the development of functional agonists and antagonists as potential therapeutic agents in the treatment of IL-6-associated diseases.…”