title: Heparanase inhibits osteoblastogenesis and shifts bone marrow progenitor cell fate in myeloma bone disease.
abstract: A major cause of morbidity in patients with multiple myeloma is the development and progression of bone disease. Myeloma bone disease is characterized by rampant osteolysis in the presence of absent or diminished bone formation. Heparanase, an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate chains, is upregulated in a variety of human cancers including multiple myeloma. We and others have shown that heparanase enhances osteoclastogenesis and bone loss. However, increased osteolysis is only one element of the spectrum of myeloma bone disease. In the present study, we hypothesized that heparanase would also affect mesenchymal cells in the bone microenvironment and investigated the effect of heparanase on the differentiation of osteoblast/stromal lineage cells. Using a combination of molecular, biochemical, cellular and in vivo approaches, we demonstrated that heparanase significantly inhibited osteoblast differentiation and mineralization, and reduced bone formation in vivo. In addition, heparanase shifts the differentiation potential of osteoblast progenitors from osteoblastogenesis to adipogenesis. Mechanistically, this shift in cell fate is due, at least in part, to heparanase-enhanced production and secretion of the Wnt signaling pathway inhibitor DKK1 by both osteoblast progenitors and myeloma cells. Collectively, these data provide important new insights into the role of heparanase in all aspects of myeloma bone disease and strongly support the use of heparanase inhibitors in the treatment of multiple myeloma.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Oncology, Nanfang Hospital, Guangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ruan
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Trotter
authors.forename: Li
authors.initials: L
authors.lastname: Nan
authors.forename: Rongcheng
authors.initials: R
authors.lastname: Luo
authors.forename: Amjad
authors.initials: A
authors.lastname: Javed
authors.forename: Ralph D
authors.initials: RD
authors.lastname: Sanderson
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Suva
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
mesh_terms: D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D010006:Osteoblasts / Q000166:cytology* / Q000201:enzymology*; D013234:Stem Cells / Q000166:cytology*; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D000099175:Heparanase
keywords: Adipogenesis; Bone disease; Bone microenvironment; Heparanase; Multiple myeloma; Osteoblastogenesis
references.citation: Cancer Res. 2003 Dec 15;63(24):8749-56
references.pmid: 14695190
references.citation: FEBS J. 2010 Oct;277(19):3890-903
references.pmid: 20840586
references.citation: Biochemistry. 2000 Dec 26;39(51):15659-67
references.pmid: 11123890
references.citation: Diabetes. 2012 May;61(5):1217-24
references.pmid: 22447857
references.citation: Biochem Biophys Res Commun. 2005 Dec 16;338(2):687-93
references.pmid: 16216218
references.citation: Blood. 2009 Jan 15;113(3):517-25
references.pmid: 18687985
references.citation: Nat Rev Endocrinol. 2011 Apr;7(4):208-18
references.pmid: 21200394
references.citation: J Manag Care Pharm. 2008 Sep;14(7 Suppl):7-11
references.pmid: 18774880
references.citation: J Biol Chem. 2007 May 4;282(18):13326-33
references.pmid: 17347152
references.citation: Leukemia. 2009 Mar;23(3):435-41
references.pmid: 19039321
references.citation: Exp Hematol. 2004 Aug;32(8):685-91
references.pmid: 15308315
references.citation: Bioessays. 2012 Nov;34(11):953-62
references.pmid: 22930599
references.citation: Blood. 2010 Mar 25;115(12):2449-57
references.pmid: 20097882
references.citation: Diabetologia. 2010 Mar;53(3):536-40
references.pmid: 19943155
references.citation: Bone. 2011 Jan;48(1):6-15
references.pmid: 20643235
references.citation: J Cell Biochem. 2009 Feb 15;106(3):353-62
references.pmid: 19127541
references.citation: Blood. 2007 Jun 1;109(11):4914-23
references.pmid: 17339423
references.citation: Blood. 2000 Oct 1;96(7):2528-36
references.pmid: 11001907
references.citation: Leukemia. 2007 Jul;21(7):1580-4
references.pmid: 17377589
references.citation: Cell Mol Life Sci. 2013 Jul;70(13):2331-49
references.pmid: 23178849
references.citation: Int J Cancer. 2006 Apr 1;118(7):1609-17
references.pmid: 16217746
references.citation: Curr Pharm Des. 2007;13(20):2057-73
references.pmid: 17627539
references.citation: Clin Cancer Res. 2008 Feb 1;14(3):668-76
references.pmid: 18212251
references.citation: Blood. 2005 Feb 1;105(3):1303-9
references.pmid: 15471949
references.citation: J Biol Chem. 2008 Nov 21;283(47):32628-36
references.pmid: 18812315
references.citation: Blood. 2002 Jul 15;100(2):610-7
references.pmid: 12091355
references.citation: Cell. 2012 Jun 8;149(6):1192-205
references.pmid: 22682243
references.citation: Cancer. 2008 Sep 1;113(5):1004-11
references.pmid: 18618498
references.citation: J Gastrointest Surg. 2008 Oct;12(10):1674-81; discussion 1681-2
references.pmid: 18704599
references.citation: Cancer Res. 2010 Nov 1;70(21):8329-38
references.pmid: 20978204
references.citation: Clin Orthop Relat Res. 1996 Mar;(324):24-8
references.pmid: 8595763
references.citation: Oncol Res. 2008;17(4):183-9
references.pmid: 18773863
references.citation: Blood. 2007 Sep 15;110(6):2041-8
references.pmid: 17536013
references.citation: Calcif Tissue Int. 2012 Aug;91(2):139-48
references.pmid: 22752619
references.citation: J Cell Sci. 2006 Jun 15;119(Pt 12):2613-2620
references.pmid: 16763196
references.citation: Neoplasia. 2008 Feb;10(2):125-30
references.pmid: 18283334
references.citation: Methods Mol Biol. 2012;816:19-29
references.pmid: 22130919