title: Investigation of osteoclastogenic signalling of the RANKL substitute LIGHT.
abstract: LIGHT (TNFSF14) is a member of the TNF superfamily and is known to substitute for RANKL to induce osteoclast differentiation. LIGHT binds HVEM and LTβR, but it is not known whether these receptors play a role in osteoclast formation or whether LIGHT acts via RANKL signalling pathways. We found that both RANKL and LIGHT strongly induced phosphorylation of Akt and NFκB but not JNK in mouse osteoclast precursor cells. The addition of an Akt inhibitor showed decreased osteoclast differentiation and resorption mediated by both RANKL and LIGHT. RT-PCR and FACS analysis showed that CD14(+) human osteoclast precursors expressed HVEM and LTβR; expression levels of HVEM increased in the course of osteoclastogenesis and a decrease in LIGHT expression was associated with an increase in HVEM suggesting that there is a feedback loop related to this receptor. Our findings show that LIGHT is not inhibited by the soluble RANKL receptor OPG and that LIGHT is a potent osteoclastogenesis factor that activates the Akt, NFκB and JNK pathways.
authors: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Nuffield Orthopaedic Centre, Oxford OX3 7HE, United Kingdom.
authors: F
authors: F
authors: Hemingway
authors: T G
authors: TG
authors: Kashima
authors: H J
authors: HJ
authors: Knowles
authors: N A
authors: NA
authors: Athanasou
mesh_terms: D002454:Cell Differentiation; D002478:Cells, Cultured; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism*; D053244:Osteoprotegerin / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism*
chemical_list: D018950:Lipopolysaccharide Receptors; D053259:Lymphotoxin beta Receptor; D016328:NF-kappa B; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D053240:Receptors, Tumor Necrosis Factor, Member 14; C505686:TNFRSF11A protein, human; C506028:TNFRSF14 protein, human; C505688:TNFSF11 protein, human; C505914:TNFSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases