title: Leptin inhibits osteoclast generation.
abstract: Originally, leptin was described as a product of adipocytes that acts on the hypothalamus to regulate appetite. However, subsequently, it has been shown that leptin receptors are distributed widely and that leptin has diverse functions, including promotion of hemopoietic and osteoblastic differentiation. It has been recognized for some time that both serum leptin and bone mass are correlated positively to body fat mass and, recently, we have shown a direct positive relationship between serum leptin and bone mass in nonobese women. We now report that leptin inhibits osteoclast generation in cultures of human peripheral blood mononuclear cells (PBMCs) and murine spleen cells incubated on bone in the presence of human macrophage colony-stimulating factor (hM-CSF) and human soluble receptor activator of NF-kappaB ligand (sRANKL). The half-maximal concentration inhibitory of leptin was approximately 20 nM in the presence of sRANKL at 40 ng/ml but decreased to approximately 2 nM when sRANKL was used at 5 ng/ml. The majority of the inhibitory effect occurred in the first week of the 3-week cultures. Inhibition did not occur when the PBMC cultures were washed vigorously to remove nonadherent cells or when purified CD14+ monocytes were used to generate osteoclasts, indicating an indirect or permissive effect via CD14- PBMC. Leptin increased osteoprotegerin (OPG) messenger RNA (mRNA) and protein expression in PBMC but not in CD14+ cells, suggesting that the inhibitory effect may be mediated by the RANKL/RANK/OPG system. Leptin may act locally to increase bone mass and may contribute to linkage of bone formation and resorption.
authors.affiliation: Department of Clinical and Biomedical Sciences: Barwon Health, The Geelong Hospital, The University of Melbourne, Australia.
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Holloway
authors.forename: Fiona McL
authors.initials: FM
authors.lastname: Collier
authors.forename: Cathy J
authors.initials: CJ
authors.lastname: Aitken
authors.forename: Damian E
authors.initials: DE
authors.lastname: Myers
authors.forename: Jason M
authors.initials: JM
authors.lastname: Hodge
authors.forename: Mary
authors.initials: M
authors.lastname: Malakellis
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Gough
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Collier
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Nicholson
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000166:cytology; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation; D002478:Cells, Cultured; D006023:Glycoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D009000:Monocytes / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin; D018124:Receptors, Tumor Necrosis Factor; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; C515448:LEPR protein, human; D020738:Leptin; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D054411:Receptors, Leptin; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; C515447:leptin receptor, mouse; D016173:Macrophage Colony-Stimulating Factor