title: Immunomodulatory drugs lenalidomide and pomalidomide inhibit multiple myeloma-induced osteoclast formation and the RANKL/OPG ratio in the myeloma microenvironment targeting the expression of adhesion molecules.
abstract: Multiple myeloma (MM)-induced osteoclast (OC) formation is mainly due to an imbalance of the receptor activator NF-κB ligand (RANKL)-osteoprotegerin (OPG) ratio in favor of RANKL in the bone microenvironment and to the CCL3 production by MM cells. The purpose of the study was to investigate the effect of the immunomodulatory drugs on RANKL/OPG ratio, the production of pro-osteoclastogenic cytokines, and MM-induced OC formation. We found that in vivo concentrations of both lenalidomide (LEN) and pomalidomide (POM) significantly blunted RANKL upregulation normalizing the RANKL/OPG ratio in human osteoprogenitor cells (PreOBs) when co-cultured with MM cells and also inhibited CCL3 production by MM cells. A reduction in CD49d expression, a molecule critically involved in RANKL upregulation in the MM microenvironment, accompanied this effect. Consistently, the pro-osteoclastogenic property of MM cells co-cultured with PreOBs was reduced by both LEN and POM. We further investigated the effect of these drugs on the transcriptional profile of both MM cells and PreOBs by microarray analysis, which showed that adhesion molecules, such as ITGA8 and ICAM2, are significantly downregulated in MM cells. Our data suggest that LEN and POM inhibit MM-induced OC formation through normalization of the RANKL/OPG ratio targeting the expression of adhesion molecules by MM cells.
authors.affiliation: Hematology and BMT Center, University of Parma, Parma, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Bolzoni
authors.forename: Paola
authors.initials: P
authors.lastname: Storti
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bonomini
authors.forename: Katia
authors.initials: K
authors.lastname: Todoerti
authors.forename: Daniela
authors.initials: D
authors.lastname: Guasco
authors.forename: Denise
authors.initials: D
authors.lastname: Toscani
authors.forename: Luca
authors.initials: L
authors.lastname: Agnelli
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rizzoli
authors.forename: Nicola
authors.initials: N
authors.lastname: Giuliani
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D039441:Integrin alpha4 / Q000235:genetics / Q000378:metabolism; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D053244:Osteoprotegerin / Q000235:genetics* / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D054405:Chemokine CCL3; D007155:Immunologic Factors; D053244:Osteoprotegerin; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D039441:Integrin alpha4; D013792:Thalidomide; C467566:pomalidomide; D000077269:Lenalidomide