title: Interleukin-34 is expressed by giant cell tumours of bone and plays a key role in RANKL-induced osteoclastogenesis.
abstract: Interleukin-34 (IL-34) is a newly discovered regulator of myeloid lineage differentiation, proliferation, and survival, acting via the macrophage-colony stimulating factor receptor (M-CSF receptor, c-fms). M-CSF, the main ligand for c-fms, is required for osteoclastogenesis and has been already identified as a critical contributor of the pathogenesis of giant cell tumours of bone (GCTs), tumours rich in osteoclasts. According to the key role of M-CSF in osteoclastogenesis and GCTs, the expression of IL-34 in human GCTs was first assessed. Quantitative analysis of IL-34 mRNA expression in 14 human GCTs revealed expression of this cytokine in GCTs as well as M-CSF and c-fms. Immunohistochemistry demonstrated that osteoclast-like cells exhibited a huge immunostaining for IL-34 and that mononuclear stromal cells were slightly positive for this protein. In contrast to osteoblasts, bone-resorbing osteoclasts showed very strong staining for IL-34, suggesting its potential role in the pathogenesis of GCTs by facilitating osteoclast formation. The role of IL-34 in osteoclastogenesis was then studied in murine and human models. IL-34 was able to support RANKL-induced osteoclastogenesis in the absence of M-CSF in all models. Multinucleated cells generated in the presence of IL-34 and RANKL expressed specific osteoclastic markers and resorbed dentine. IL-34 induced phosphorylation of ERK 1/2 and Akt through the activation of c-fms, as revealed by the inhibition of signalling by a specific c-fms tyrosine kinase inhibitor. Furthermore, IL-34 stimulated RANKL-induced osteoclastogenesis by promoting the adhesion and proliferation of osteoclast progenitors, and had no effect on osteoclast survival. Overall, these data reveal that IL-34 can be entirely substituted for M-CSF in RANKL-induced osteoclastogenesis, thus identifying a new biological activity for this cytokine and a contribution to the pathogenesis of GCTs.
authors.affiliation: INSERM, UMR-S 957, Nantes F-44035, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Baud'huin
authors.forename: Romain
authors.initials: R
authors.lastname: Renault
authors.forename: Céline
authors.initials: C
authors.lastname: Charrier
authors.forename: Anne
authors.initials: A
authors.lastname: Riet
authors.forename: Anne
authors.initials: A
authors.lastname: Moreau
authors.forename: Régis
authors.initials: R
authors.lastname: Brion
authors.forename: François
authors.initials: F
authors.lastname: Gouin
authors.forename: Laurence
authors.initials: L
authors.lastname: Duplomb
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology; D039481:CD11b Antigen / Q000032:analysis; D018286:Carcinoma, Giant Cell / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D053245:RANK Ligand / Q000494:pharmacology / Q000502:physiology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D055815:Young Adult
chemical_list: C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; D039481:CD11b Antigen; C529076:IL34 protein, human; D007378:Interleukins; D009363:Neoplasm Proteins; D011743:Pyrimidines; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D016186:Receptor, Macrophage Colony-Stimulating Factor