Oncostatin M A. Gregory Bruce and Timothy M. Rose* Department of Pathobiology, School of Public Health and Community Medicine, University of Washington, Box 357238, Seattle, WA 98195, USA * corresponding author tel: 206-616-2084, fax: 206-543-3873, e-mail: trose@u.washington.edu DOI: 10.1006/rwcy.2000.06005. SUMMARY Oncostatin M (OSM) is a pleiotropic cytokine within the IL-6 family of cytokines which regulates cell growth and differentiation in a wide variety of bio- logical systems, including hematopoiesis, neurogenesis, and osteogenesis. BACKGROUND Discovery Oncostatin M (OSM) was originally discovered as a protein which inhibited the proliferation of a number of human tumor cell lines, but not normal human fibroblasts. It was isolated from supernatants of U- 937 human histiocytic leukemia cells that were induced to differentiate into macrophage-like cells by treatment with phorbol 12-myristate 13-acetate (PMA) (Zarling et al., 1986). Human, simian, bovine, and murine forms of OSM have been cloned and characterized. OSM has been shown by sequence homology and structural and functional similarities to be closely related to leukemia inhibitory factor (LIF) and other members of the IL-6 family of cytokines, including IL-6, IL-11, ciliary neurotropic factor (CNTF), and cardiotropin 1 (CT-1) (Bazan, 1991; Rose and Bruce, 1991). Alternative names A number of abbreviations for oncostatin M have been used in the literature, including OSM, OM, Onco M, and ONC, although OSM is the preferred abbreviation. There are no other factors that have subsequently been shown to be OSM. Structure Human OSM is a secreted glycoprotein which is initially translated as a 252 amino acid polypeptide with a 25 residue hydrophobic signal sequence at the N-terminus that is removed during the secretion pro- cess. An additional posttranslational cleavage removes 31 C-terminal residues, resulting in a 192 amino acid disulfide-linked mature protein. OSM adopts a four -helical bundle structure with up-up-down-down topology similar to that determined for other cyto- kines and growth factors (Rose and Bruce, 1991; Robinson et al., 1994). Main activities and pathophysiological roles OSM has been shown to be a pleiotropic cytokine which regulates cell growth and differentiation in a wide variety of biological systems including hemato- poiesis, neurogenesis, and osteogenesis (Bruce et al., 1992b). The elaboration of the biological activities of OSM has been confounded by the presence of different OSM receptor signaling systems in humans and mice. In humans, OSM signals through two different receptors complexes; the LIF/OSM shared receptor (Gearing and Bruce, 1992), which shares high-affinity binding with LIF, an evolutionarily related protein with structural similarity to OSM (Rose and Bruce, 1991), and the OSM-specific receptor which binds OSM uniquely (Bruce et al., 1992b). In mice, OSM signals only through the murine homolog of the OSM-specific receptor (Ichihara et al., 1997; Lindberg et al., 1998). To confuse matters, human OSM, used historically for in vitro and in vivo studies in mice, binds uniquely to the murine LIF