title: Human myeloma cells stimulate the receptor activator of nuclear factor-kappa B ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease.
abstract: The biologic mechanisms involved in the pathogenesis of multiple myeloma (MM) bone disease are not completely understood. Recent evidence suggests that T cells may regulate bone resorption through the cross-talk between the critical osteoclastogenetic factor, receptor activator of nuclear factor-kappaB ligand (RANKL), and interferon gamma (IFN-gamma) that strongly suppresses osteoclastogenesis. Using a coculture transwell system we found that human myeloma cell lines (HMCLs) increased the expression and secretion of RANKL in activated T lymphocytes and similarly purified MM cells stimulated RANKL production in autologous T lymphocytes. In addition, either anti-interleukin 6 (anti-IL-6) or anti-IL-7 antibody inhibited HMCL-induced RANKL overexpression. Consistently, we demonstrated that HMCLs and fresh MM cells express IL-7 mRNA and secrete IL-7 in the presence of IL-6 and that bone marrow (BM) IL-7 levels were significantly higher in patients with MM. Moreover, we found that the release of IFN-gamma by T lymphocytes was reduced in presence of both HMCLs and purified MM cells. Furthermore, in a stromal cell-free system, osteoclastogenesis was stimulated by conditioned medium of T cells cocultured with HMCLs and inhibited by recombinant human osteoprotegerin (OPG; 100 ng/mL to 1 microg/mL). Finally, RANKL mRNA was up-regulated in BM T lymphocytes of MM patients with severe osteolytic lesions, suggesting that T cells could be involved at least in part in MM-induced osteolysis through the RANKL overexpression.
authors.affiliation: Hematology Department of Internal Medicine and Biomedical Science, University of Parma, Parma, Italy. nicola.giuliani@unipr.it
authors.forename: Nicola
authors.initials: N
authors.lastname: Giuliani
authors.forename: Simona
authors.initials: S
authors.lastname: Colla
authors.forename: Roberto
authors.initials: R
authors.lastname: Sala
authors.forename: Matteo
authors.initials: M
authors.lastname: Moroni
authors.forename: Mirca
authors.initials: M
authors.lastname: Lazzaretti
authors.forename: Silvia
authors.initials: S
authors.lastname: La Monica
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bonomini
authors.forename: Magda
authors.initials: M
authors.lastname: Hojden
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sammarelli
authors.forename: Sophie
authors.initials: S
authors.lastname: Barillè
authors.forename: Regis
authors.initials: R
authors.lastname: Bataille
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rizzoli
mesh_terms: D000368:Aged; D001854:Bone Marrow Cells / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D015851:Interleukin-7 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology; D010014:Osteolysis / Q000209:etiology*; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000494:pharmacology; D017154:Stromal Cells / Q000166:cytology; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D006023:Glycoproteins; D015850:Interleukin-6; D015851:Interleukin-7; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human