title: Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma.
abstract: Osteolytic bone disease in multiple myeloma (MM) is caused by enhanced osteoclast (OCL) activation and inhibition of osteoblast function. Lenalidomide and bortezomib have shown promising response rates in relapsed and newly diagnosed MM, and bortezomib has recently been reported to inhibit OCLs. We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib. Both drugs decreased alpha V beta 3-integrin, tartrate-resistant acid phosphatase-positive cells and bone resorption on dentin disks. In addition, both agents decreased receptor activator of nuclear factor-kappaB ligand (RANKL) secretion of bone marrow stromal cells (BMSCs) derived from MM patients. We identified PU.1 and pERK as major targets of lenalidomide, and nuclear factor of activated T cells of bortezomib, resulting in inhibition of osteoclastogenesis. Furthermore, downregulation of cathepsin K, essential for resorption of the bone collagen matrix, was observed. We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein-alpha, B-cell activating factor and a proliferation-inducing ligand. Importantly, in serum from MM patients treated with lenalidomide, the essential bone-remodeling factor RANKL, as well as the RANKL/OPG ratio, were significantly reduced, whereas osteoprotegerin (OPG) was increased. We conclude that both agents specifically target key factors in osteoclastogenesis, and could directly affect the MM-OCL-BMSCs activation loop in osteolytic bone disease.
authors.affiliation: Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Iris_Breitkreutz@dfci.harvard.edu
authors.forename: I
authors.initials: I
authors.lastname: Breitkreutz
authors.forename: M S
authors.initials: MS
authors.lastname: Raab
authors.forename: S
authors.initials: S
authors.lastname: Vallet
authors.forename: T
authors.initials: T
authors.lastname: Hideshima
authors.forename: N
authors.initials: N
authors.lastname: Raje
authors.forename: C
authors.initials: C
authors.lastname: Mitsiades
authors.forename: D
authors.initials: D
authors.lastname: Chauhan
authors.forename: Y
authors.initials: Y
authors.lastname: Okawa
authors.forename: N C
authors.initials: NC
authors.lastname: Munshi
authors.forename: P G
authors.initials: PG
authors.lastname: Richardson
authors.forename: K C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D053264:B-Cell Activating Factor / Q000378:metabolism; D016723:Bone Remodeling / Q000187:drug effects*; D001862:Bone Resorption / Q000517:prevention & control; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D056657:Cathepsin K; D002403:Cathepsins / Q000032:analysis; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000032:analysis; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000188:drug therapy*; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D053244:Osteoprotegerin / Q000097:blood; D011518:Proto-Oncogene Proteins / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology; D053245:RANK Ligand / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D015534:Trans-Activators / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D000970:Antineoplastic Agents; D053264:B-Cell Activating Factor; D001897:Boronic Acids; D000069286:Bortezomib; D056657:Cathepsin K; D002403:Cathepsins; D054405:Chemokine CCL3; D039302:Integrin alphaVbeta3; D000077269:Lenalidomide; D053244:Osteoprotegerin; D011518:Proto-Oncogene Proteins; D011719:Pyrazines; D053245:RANK Ligand; D013792:Thalidomide; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D000099232:Proto-Oncogene Protein Spi-1; C515429:CCL3 protein, human; C505688:TNFSF11 protein, human; C114631:TNFSF13 protein, human; C505719:TNFSF13B protein, human; C534130:CTSK protein, human