The Role of IL-6 Type Cytokines and Their Receptors in Boneaa



    Corresponding author
    1. Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, the UAMS Center for Osteoporosis and Metabolic Bone Diseases, and the GRECC of the McClellan VA Medical Center, Little Rock, Arkansas 77205 USA
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    This work was supported by the National Institutes of Health (P01 AG/AR 13918 and AR 43003) and the Department of Veterans Affairs.

Address for correspondence: Stavros C. Manolagas, M. D., Ph. D., University of Arkansas for Medical Sciences, 4301 West Markham, Mail Slot 587, Little Rock, Arkansas 72205. Telephone: 501-686-5130; Fax: 501-686-8148


Abstract: Substantial evidence indicates that the IL-6 type of cytokines have profound effects on bone metabolism by regulating osteoclast and osteoblast development and function. In addition, there is evidence that the gp130 signal transduction pathway may be a critical site for the regulation of the rate of bone remodeling, and probably the coupling of bone resorption to bone formation. Sex steroids inhibit the expression of the genes encoding IL-6, gp80, and gp130, most likely by repressing the activity of transcription factors such as NFκB and NF-IL-6. Considering this and the evidence that IL-6 autoregulates its own production and can upregulate the components of its receptor, removal of the direct inhibitory effects of sex steroids on IL-6, gp80, and gp130 could unleash a self-amplifying cascade of events responsible for increasing not only the production of IL-6, but also the responsiveness of osteoclast progenitors, osteoblast progenitors, and stromal/osteoblastic cells that support osteoclastogenesis, or combinations of these cells, to IL-6 type cytokines. Such a scenario could explain both the increased osteoclastogenesis and osteoblastogenesis that follows loss of gonadal function and thereby the effect of such loss on the rate of bone remodeling and skeletal homeostasis. Manipulation of the effects of IL-6 type cytokines, by selectively targeting to specific bone cell precursors, may allow means of altering the balance between bone resorption and formation in favor of the latter.