title: Endogenous production of TGF-beta is essential for osteoclastogenesis induced by a combination of receptor activator of NF-kappa B ligand and macrophage-colony-stimulating factor.
abstract: Differentiation of osteoclasts, the cells primarily responsible for bone resorption, is controlled by a variety of osteotropic hormones and cytokines. Of these factors, receptor activator of NF-kappaB (RANK) ligand (RANKL) has been recently cloned as an essential inducer of osteoclastogenesis in the presence of M-CSF. Here, we isolated a stroma-free population of monocyte/macrophage (M/Mphi)-like hemopoietic cells from mouse unfractionated bone cells that were capable of differentiating into mature osteoclasts by treatment with soluble RANKL (sRANKL) and M-CSF. However, the efficiency of osteoclast formation was low, suggesting the requirement for additional factors. The isolated M/Mphi-like hemopoietic cells expressed TGF-beta and type I and II receptors of TGF-beta. Therefore, we examined the effect of TGF-beta on osteoclastogenesis. TGF-beta with a combination of sRANKL and M-CSF promoted the differentiation of nearly all M/Mphi-like hemopoietic cells into cells of the osteoclast lineage. Neutralizing anti-TGF-beta Ab abrogated the osteoclast generation. These TGF-beta effects were also observed in cultures of unfractionated bone cells, and anti-TGF-beta blocked the stimulatory effect of 1, 25-dihydroxyvitamin D(3). Translocation of NF-kappaB into nuclei induced by sRANKL in TGF-beta-pretreated M/Mphi-like hemopoietic cells was greater than that in untreated cells, whereas TGF-beta did not up-regulate the expression of RANK, the receptor of RANKL. Our findings suggest that TGF-beta is an essential autocrine factor for osteoclastogenesis.
authors.affiliation: Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kaneda
authors.forename: T
authors.initials: T
authors.lastname: Nojima
authors.forename: M
authors.initials: M
authors.lastname: Nakagawa
authors.forename: A
authors.initials: A
authors.lastname: Ogasawara
authors.forename: H
authors.initials: H
authors.lastname: Kaneko
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.forename: H
authors.initials: H
authors.lastname: Mano
authors.forename: M
authors.initials: M
authors.lastname: Kumegawa
authors.forename: Y
authors.initials: Y
authors.lastname: Hakeda
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins; D002454:Cell Differentiation / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D004357:Drug Synergism; D006023:Glycoproteins / Q000494:pharmacology / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D008813:Mice, Inbred ICR; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000494:pharmacology / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D016212:Transforming Growth Factor beta; D016173:Macrophage Colony-Stimulating Factor