title: Osteoclast-derived matrix metalloproteinase-7, but not matrix metalloproteinase-9, contributes to tumor-induced osteolysis.
abstract: The matrix metalloproteinases MMP-2, MMP-3, MMP-7, MMP-9, and MMP-13 are highly expressed in the tumor-bone microenvironment, and, of these, MMP-7 and MMP-9 were found to be localized to bone-resorbing osteoclasts in human breast-to-bone metastases. In a bid to define the roles of host-derived MMP-7 and MMP-9 in the tumor-bone microenvironment, the tibias of MMP-7 and MMP-9 null mice were injected with osteolytic luciferase-tagged mammary tumor cell lines. Our data show that osteoclast-derived MMP-7 significantly contributes to tumor growth and tumor-induced osteolysis whereas osteoclast-derived MMP-9 had no effect on these processes. MMP-7 is capable of processing a number of nonmatrix molecules to soluble active forms that have profound effects on cell-cell communication, such as RANKL, a crucial mediator of osteoclast precursor recruitment and maturation. Therefore, the ability of osteoclast-derived MMP-7 to promote RANKL solubilization in the tumor-bone microenvironment was explored. Results revealed that levels of soluble RANKL were significantly lower in the MMP-7 null mice compared with wild-type (WT) controls. In keeping with this observation, MMP-7 null mice had significantly fewer osteoclast numbers at the tumor-bone interface compared with the WT controls. In summary, we propose that the solubilization of RANKL by MMP-7 is a potential mechanism through which MMP-7 mediates mammary tumor-induced osteolysis. Our studies indicate that the selective inhibition of MMP-7 in the tumor-bone microenvironment may be of benefit for the treatment of lytic breast-to-bone metastases.
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Thiolloy
authors.forename: Jennifer
authors.initials: J
authors.lastname: Halpern
authors.forename: Ginger E
authors.initials: GE
authors.lastname: Holt
authors.forename: Herbert S
authors.initials: HS
authors.lastname: Schwartz
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Mundy
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Matrisian
authors.forename: Conor C
authors.initials: CC
authors.lastname: Lynch
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics; D001859:Bone Neoplasms / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism*; D010014:Osteolysis / Q000209:etiology* / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D053245:RANK Ligand; D020783:Matrix Metalloproteinase 7; D020780:Matrix Metalloproteinase 9
references.citation: Lab Invest. 1998 Jan;78(1):79-87
references.pmid: 9461124
references.citation: Nature. 1999 Jan 28;397(6717):315-23
references.pmid: 9950424
references.citation: Nat Cell Biol. 2000 Oct;2(10):737-44
references.pmid: 11025665
references.citation: Science. 2002 Mar 29;295(5564):2387-92
references.pmid: 11923519
references.citation: Bioessays. 1998 Oct;20(10):837-46
references.pmid: 9819571
references.citation: Science. 1999 Oct 1;286(5437):113-7
references.pmid: 10506557
references.citation: Clin Chim Acta. 2000 Feb 15;291(2):223-34
references.pmid: 10675725
references.citation: Am J Pathol. 2003 Oct;163(4):1233-43
references.pmid: 14507633
references.citation: J Histochem Cytochem. 2004 Mar;52(3):411-4
references.pmid: 14966208
references.citation: Cancer Res. 2006 Jan 1;66(1):259-66
references.pmid: 16397239
references.citation: Differentiation. 2002 Dec;70(9-10):561-73
references.pmid: 12492497
references.citation: J Cell Biol. 2000 Nov 13;151(4):879-89
references.pmid: 11076971
references.citation: Clin Exp Metastasis. 2006;23(7-8):345-56
references.pmid: 17136574
references.citation: Microsc Res Tech. 2003 Aug 15;61(6):504-13
references.pmid: 12879418
references.citation: J Biol Chem. 1999 May 7;274(19):13613-8
references.pmid: 10224132
references.citation: Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1402-7
references.pmid: 9037065
references.citation: J Mammary Gland Biol Neoplasia. 1998 Apr;3(2):177-89
references.pmid: 10819526
references.citation: Biochem J. 1997 Mar 15;322 ( Pt 3):809-14
references.pmid: 9148753
references.citation: Clin Cancer Res. 2002 Jun;8(6):1932-9
references.pmid: 12060638
references.citation: J Endocrinol. 2002 Jun;173(3):387-94
references.pmid: 12065228
references.citation: J Biol Chem. 2001 May 4;276(18):14665-74
references.pmid: 11278735
references.citation: Cancer Res. 2008 Jul 15;68(14):5803-11
references.pmid: 18632634
references.citation: Crit Rev Eukaryot Gene Expr. 2000;10(2):159-78
references.pmid: 11186331
references.citation: Hybridoma (Larchmt). 2007 Feb;26(1):22-7
references.pmid: 17316082
references.citation: Microb Pathog. 2005 Feb-Mar;38(2-3):97-105
references.pmid: 15748811
references.citation: Eur J Cancer. 2001 Jan;37(1):106-13
references.pmid: 11165137
references.citation: J Clin Invest. 2000 Jan;105(2):143-50
references.pmid: 10642592
references.citation: Neoplasia. 2001 Nov-Dec;3(6):459-68
references.pmid: 11774028
references.citation: Cancer Res. 2008 Aug 1;68(15):6251-9
references.pmid: 18676849
references.citation: J Natl Cancer Inst. 1997 Sep 3;89(17):1260-70
references.pmid: 9293916
references.citation: Cancer Cell. 2005 May;7(5):485-96
references.pmid: 15894268
references.citation: FASEB J. 2003 Sep;17(12):1751-3
references.pmid: 12958198
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19327-32
references.pmid: 18042722
references.citation: Clin Exp Metastasis. 2006;23(7-8):335-44
references.pmid: 17136575
references.citation: Histol Histopathol. 1999 Apr;14(2):635-47
references.pmid: 10212824
references.citation: Nat Rev Cancer. 2002 Aug;2(8):584-93
references.pmid: 12154351
references.citation: J Natl Cancer Inst. 2002 Jan 2;94(1):17-25
references.pmid: 11773278
references.citation: Cancer Res. 1992 Mar 15;52(6):1399-405
references.pmid: 1540948
references.citation: Br J Cancer. 1987 Jan;55(1):61-6
references.pmid: 3814476
references.citation: Curr Biol. 1999 Dec 16-30;9(24):1441-7
references.pmid: 10607586
references.citation: Cancer Res. 2004 Jan 15;64(2):665-71
references.pmid: 14744783
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13453-8
references.pmid: 9811821
references.citation: J Biol Chem. 2001 Jul 27;276(30):28261-7
references.pmid: 11375993