title: Inhibition of Transforming Growth Factor-β Activation Diminishes Tumor Progression and Osteolytic Bone Disease in Mouse Models of Multiple Myeloma.
abstract: Transforming growth factor (TGF)-β supports multiple myeloma progression and associated osteolytic bone disease. Conversion of latent TGF-β to its biologically active form is a major regulatory node controlling its activity. Thrombospondin1 (TSP1) binds and activates TGF-β. TSP1 is increased in myeloma, and TSP1-TGF-β activation inhibits osteoblast differentiation. We hypothesized that TSP1 regulates TGF-β activity in myeloma and that antagonism of the TSP1-TGF-β axis inhibits myeloma progression. Antagonists (LSKL peptide, SRI31277) derived from the LSKL sequence of latent TGF-β that block TSP1-TGF-β activation were used to determine the role of the TSP1-TGF-β pathway in mouse models of myeloma. TSP1 binds to human myeloma cells and activates TGF-β produced by cultured human and mouse myeloma cell lines. Antagonists delivered via osmotic pump in an intratibial severe combined immunodeficiency CAG myeloma model or in a systemic severe combined immunodeficiency CAG-heparanase model of aggressive myeloma reduced TGF-β signaling (phospho-Smad 2) in bone sections, tumor burden, mouse IL-6, and osteoclasts, increased osteoblast number, and inhibited bone destruction as measured by microcomputed tomography. SRI31277 reduced tumor burden in the immune competent 5TGM1 myeloma model. SRI31277 was as effective as dexamethasone or bortezomib, and SRI31277 combined with bortezomib showed greater tumor reduction than either agent alone. These studies validate TSP1-regulated TGF-β activation as a therapeutic strategy for targeted inhibition of TGF-β in myeloma.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Ailing
authors.initials: A
authors.lastname: Lu
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Pallero
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Weiqi
authors.initials: W
authors.lastname: Lei
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Huixian
authors.initials: H
authors.lastname: Hong
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Southern Research, Birmingham, Alabama.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Suto
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address: murphy@uab.edu.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Murphy-Ullrich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000069286:Bortezomib / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D010014:Osteolysis / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D019700:Thrombospondin 1 / Q000187:drug effects* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; C487834:Leu-Ser-Lys-Leu peptide; D010455:Peptides; C000609657:SRI31277; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; C577686:interleukin-6, mouse; C585483:Thbs1 protein, mouse; D000069286:Bortezomib