title: Transforming growth factor-beta induces osteoclast formation in the absence of RANKL.
abstract: Transforming growth factor beta (TGFbeta) is a multifunctional growth factor that is produced by many cells in bone and is abundant in the bone matrix. TGFbeta is known to regulate RANKL-induced osteoclast formation and bone resorbing activity. In this study we sought to determine whether TGFbeta could directly induce osteoclast formation by a RANKL-independent mechanism. We found that the addition of TGFbeta to cultures of human monocytes and RAW 264.7 cells (in the presence of M-CSF and the absence of RANKL, TNFalpha or IL-6/IL-11) was sufficient to induce the formation of TRAP+ and VNR+ cells, which formed actin rings and were capable of extensive lacunar resorption. The addition of osteoprotegerin or antibodies to TNFalpha and its receptors, as well as antibodies to gp130, did not inhibit lacunar resorption, indicating that TGFbeta did not act by stimulating RANKL, TNF or IL-6 production by monocytes. TGFbeta-induced osteoclast formation was qualitatively different from that induced by RANKL with numerous TRAP+/VNR+ mononuclear and small multinucleated cells being formed; these cells produced many small resorption lacunae. Our results indicate that TGFbeta, which is abundant in the bone matrix, can, in the presence of M-CSF, directly induce mononuclear phagocyte osteoclast precursors to differentiate into osteoclastic cells capable of lacunar resorption.
authors.affiliation: Nuffield Department of Orthopaedic Surgery, University of Oxford, Oxford OX3 7LD, UK.
authors.forename: I
authors.initials: I
authors.lastname: Itonaga
authors.forename: A
authors.initials: A
authors.lastname: Sabokbar
authors.forename: S G
authors.initials: SG
authors.lastname: Sun
authors.forename: O
authors.initials: O
authors.lastname: Kudo
authors.forename: L
authors.initials: L
authors.lastname: Danks
authors.forename: D
authors.initials: D
authors.lastname: Ferguson
authors.forename: Y
authors.initials: Y
authors.lastname: Fujikawa
authors.forename: N A
authors.initials: NA
authors.lastname: Athanasou
mesh_terms: D000199:Actins / Q000378:metabolism; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D050822:Cytokine Receptor gp130; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000276:immunology / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology*
chemical_list: D000199:Actins; D015703:Antigens, CD; D002352:Carrier Proteins; D006023:Glycoproteins; C494199:IL6ST protein, human; D007375:Interleukin-1; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D016212:Transforming Growth Factor beta; D050822:Cytokine Receptor gp130