A number of cytokines have been shown to play an essential role in bone remodeling. These local modulators have often been implicated in common diseases such as osteoporosis, osteoporosis, Paget's disease, periodontal disease and rheumatoid arthritis, which share as one common element defects in bone remodeling. The cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF), for example, manifest potent bone resorbing effects, and play key roles in periodontal tissue breakdown. Although many studies have been performed relative to several bone resorbing cytokines as regulator of the development and function of bone resorbing osteoclasts, little is known about the nature, relative number of distribution of cytokine receptors present in osteoclasts and their precursors. The long term focus of our effort is to unveil the mechanism of cytokine-mediated regulation of osteoclast activity. Such information should enhance our understanding of the cell and molecular processes associated with normal and inflammatory mediated bone loss. Therefore, the specific aims of this project are directed toward the identification of cytokine receptors in osteoclasts, their characterization at the molecular level, and their regulation by modulators of osteoclast formation, differentiation and/or resorption activity. Initial experiments will focus on the IL-1 receptor, since this well characterized cytokine is one of the most potent regulators of osteoclast differentiation and function. IL-1 receptors will be identified in biologically responsive cells by biochemical, immunohistochemical and in situ hybrididization analysis. The putative IL-1 receptor will be cloned from avian osteoclasts and human osteoclast-like cells. Once cloned, studies designed to examine the developmental regulation of receptor expression and to analyze receptor regulation in mature osteoclasts will be initiated. Identification and characterization of IL-1 receptors will enable us to better understand how cytoines govern bone remodeling.
| Sunyer, T; Lewis, J; Collin-Osdoby, P et al. (1999) Estrogen's bone-protective effects may involve differential IL-1 receptor regulation in human osteoclast-like cells. J Clin Invest 103:1409-18 |
