title: Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma.
abstract: In multiple myeloma, an overabundance of monoclonal plasma cells in the bone marrow induces localized osteolytic lesions that rarely heal due to increased bone resorption and suppressed bone formation. Matrix-embedded osteocytes comprise more than 95% of bone cells and are major regulators of osteoclast and osteoblast activity, but their contribution to multiple myeloma growth and bone disease is unknown. Here, we report that osteocytes in a mouse model of human MM physically interact with multiple myeloma cells in vivo, undergo caspase-3-dependent apoptosis, and express higher RANKL (TNFSF11) and sclerostin levels than osteocytes in control mice. Mechanistic studies revealed that osteocyte apoptosis was initiated by multiple myeloma cell-mediated activation of Notch signaling and was further amplified by multiple myeloma cell-secreted TNF. The induction of apoptosis increased osteocytic Rankl expression, the osteocytic Rankl/Opg (TNFRSF11B) ratio, and the ability of osteocytes to attract osteoclast precursors to induce local bone resorption. Furthermore, osteocytes in contact with multiple myeloma cells expressed high levels of Sost/sclerostin, leading to a reduction in Wnt signaling and subsequent inhibition of osteoblast differentiation. Importantly, direct contact between osteocytes and multiple myeloma cells reciprocally activated Notch signaling and increased Notch receptor expression, particularly Notch3 and 4, stimulating multiple myeloma cell growth. These studies reveal a previously unknown role for bidirectional Notch signaling that enhances MM growth and bone disease, suggesting that targeting osteocyte-multiple myeloma cell interactions through specific Notch receptor blockade may represent a promising treatment strategy in multiple myeloma.
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana. Roudebush Veterans Administration Medical Center, Indianapolis, Indiana.
authors.forename: Jesus
authors.initials: J
authors.lastname: Delgado-Calle
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Judith
authors.initials: J
authors.lastname: Anderson
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Meloney D
authors.initials: MD
authors.lastname: Cregor
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiasa
authors.affiliation: Roudebush Veterans Administration Medical Center, Indianapolis, Indiana. Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: John M
authors.initials: JM
authors.lastname: Chirgwin
authors.affiliation: Department of Pediatrics Indiana, University School of Medicine, Indianapolis, Indiana.
authors.forename: Nadia
authors.initials: N
authors.lastname: Carlesso
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yoneda
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana. Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana. Roudebush Veterans Administration Medical Center, Indianapolis, Indiana.
authors.forename: Lilian I
authors.initials: LI
authors.lastname: Plotkin
authors.affiliation: Roudebush Veterans Administration Medical Center, Indianapolis, Indiana. Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. tbellido@iupui.edu groodman@iu.edu.
authors.forename: G David
authors.initials: GD
authors.lastname: Roodman
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana. Roudebush Veterans Administration Medical Center, Indianapolis, Indiana. Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. tbellido@iupui.edu groodman@iu.edu.
authors.forename: Teresita
authors.initials: T
authors.lastname: Bellido
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D001853:Bone Marrow / Q000502:physiology*; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D001862:Bone Resorption / Q000209:etiology*; D049109:Cell Proliferation; D060833:Cellular Microenvironment / Q000502:physiology*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000150:complications* / Q000473:pathology; D010006:Osteoblasts / Q000166:cytology; D010011:Osteocytes / Q000502:physiology*; D010012:Osteogenesis; D053245:RANK Ligand / Q000502:physiology; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D053245:RANK Ligand; D051880:Receptors, Notch; C422903:SOST protein, human; D014409:Tumor Necrosis Factor-alpha
references.citation: Leukemia. 2009 Mar;23(3):435-41
references.pmid: 19039321
references.citation: Blood. 2005 Oct 1;106(7):2472-83
references.pmid: 15933061
references.citation: Br J Haematol. 2010 Feb;148(4):551-61
references.pmid: 19919653
references.citation: J Bone Miner Metab. 2010 May;28(3):244-50
references.pmid: 20127498
references.citation: Mol Cancer Ther. 2010 Dec;9(12):3200-9
references.pmid: 21159606
references.citation: J Biol Chem. 2005 Dec 16;280(50):41342-51
references.pmid: 16251184
references.citation: Cancer Res. 2006 May 1;66(9):4715-24
references.pmid: 16651424
references.citation: Nat Rev Mol Cell Biol. 2006 Sep;7(9):678-89
references.pmid: 16921404
references.citation: Exp Hematol. 2006 Oct;34(10):1289-95
references.pmid: 16982321
references.citation: Stem Cells. 2007 Jan;25(1):203-10
references.pmid: 16973835
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3324-9
references.pmid: 17360646
references.citation: Blood. 2008 Feb 15;111(4):2220-9
references.pmid: 18039953
references.citation: Methods Mol Biol. 2008;455:51-75
references.pmid: 18463810
references.citation: J Bone Miner Res. 2008 Jun;23(6):860-9
references.pmid: 18269310
references.citation: PLoS One. 2008;3(8):e2942
references.pmid: 18698360
references.citation: J Bone Miner Res. 2011 Feb;26(2):229-38
references.pmid: 21254230
references.citation: J Cell Biochem. 2011 Sep;112(9):2412-23
references.pmid: 21538477
references.citation: J Cell Biochem. 2011 Oct;112(10):2920-30
references.pmid: 21630325
references.citation: Ann N Y Acad Sci. 2011 Nov;1237:19-23
references.pmid: 22082361
references.citation: Blood. 2011 Dec 22;118(26):6871-80
references.pmid: 22042697
references.citation: Blood. 2004 May 1;103(9):3511-5
references.pmid: 14726396
references.citation: Blood Cells Mol Dis. 2012 Apr 15;48(4):247-53
references.pmid: 22341562
references.citation: Leukemia. 2012 Jun;26(6):1402-5
references.pmid: 22094583
references.citation: Leukemia. 2012 Jun;26(6):1391-401
references.pmid: 22289923
references.citation: J Biol Chem. 2012 Jun 29;287(27):22683-90
references.pmid: 22589536
references.citation: Hum Mol Genet. 2001 Mar 1;10(5):537-43
references.pmid: 11181578
references.citation: Cell. 2001 Mar 9;104(5):719-30
references.pmid: 11257226
references.citation: J Bone Miner Res. 2001 Sep;16(9):1622-33
references.pmid: 11547831
references.citation: Exp Hematol. 2003 Apr;31(4):271-82
references.pmid: 12691914
references.citation: J Exp Med. 2004 Mar 15;199(6):805-14
references.pmid: 15024046
references.citation: Dev Biol. 2004 May 1;269(1):81-94
references.pmid: 15081359
references.citation: Int J Cancer. 2012 Sep 15;131(6):1466-71
references.pmid: 22052418
references.citation: Endocr Rev. 2012 Oct;33(5):747-83
references.pmid: 22723594
references.citation: Neoplasma. 2013;60(1):33-40
references.pmid: 23067214
references.citation: Nat Med. 2013 Feb;19(2):179-92
references.pmid: 23389618
references.citation: Bone. 2013 Jun;54(2):258-63
references.pmid: 22939943
references.citation: Leukemia. 2013 Apr;27(5):1009-18
references.pmid: 23307030
references.citation: PLoS One. 2013;8(7):e69593
references.pmid: 23869245
references.citation: Calcif Tissue Int. 2014 Jan;94(1):25-34
references.pmid: 24002178
references.citation: Leukemia. 2014 Feb;28(2):398-403
references.pmid: 24005246
references.citation: J Biol Chem. 2014 Mar 21;289(12):8508-20
references.pmid: 24509854
references.citation: Blood Cancer J. 2014;4:e217
references.pmid: 24927406
references.citation: Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):E478-86
references.pmid: 25605937
references.citation: Blood. 2015 May 14;125(20):3049-58
references.pmid: 25838343
references.citation: Oncotarget. 2015 Aug 14;6(23):19647-60
references.pmid: 25944690
references.citation: J Bone Miner Res. 1997 Dec;12(12):2014-23
references.pmid: 9421234
references.citation: J Cell Biochem. 1999 Sep 1;74(3):357-71
references.pmid: 10412038
references.citation: Blood. 2004 Dec 1;104(12):3697-704
references.pmid: 15292061
references.citation: Microsc Res Tech. 2010 Mar;73(3):182-6
references.pmid: 19725069