Osteoclast-derived matrix metalloproteinase-7, but not matrix metalloproteinase-9, contributes to tumor-induced osteolysis.
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.
Thiolloy
Sophie
S
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
Halpern
Jennifer
J
Holt
Ginger E
GE
Schwartz
Herbert S
HS
Mundy
Gregory R
GR
Matrisian
Lynn M
LM
Lynch
Conor C
CC
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
D053245:RANK Ligand; D020783:Matrix Metalloproteinase 7; D020780:Matrix Metalloproteinase 9
Lab Invest. 1998 Jan;78(1):79-87
9461124
Nature. 1999 Jan 28;397(6717):315-23
9950424
Nat Cell Biol. 2000 Oct;2(10):737-44
11025665
Science. 2002 Mar 29;295(5564):2387-92
11923519
Bioessays. 1998 Oct;20(10):837-46
9819571
Science. 1999 Oct 1;286(5437):113-7
10506557
Clin Chim Acta. 2000 Feb 15;291(2):223-34
10675725
Am J Pathol. 2003 Oct;163(4):1233-43
14507633
J Histochem Cytochem. 2004 Mar;52(3):411-4
14966208
Cancer Res. 2006 Jan 1;66(1):259-66
16397239
Differentiation. 2002 Dec;70(9-10):561-73
12492497
J Cell Biol. 2000 Nov 13;151(4):879-89
11076971
Clin Exp Metastasis. 2006;23(7-8):345-56
17136574
Microsc Res Tech. 2003 Aug 15;61(6):504-13
12879418
J Biol Chem. 1999 May 7;274(19):13613-8
10224132
Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1402-7
9037065
J Mammary Gland Biol Neoplasia. 1998 Apr;3(2):177-89
10819526
Biochem J. 1997 Mar 15;322 ( Pt 3):809-14
9148753
Clin Cancer Res. 2002 Jun;8(6):1932-9
12060638
J Endocrinol. 2002 Jun;173(3):387-94
12065228
J Biol Chem. 2001 May 4;276(18):14665-74
11278735
Cancer Res. 2008 Jul 15;68(14):5803-11
18632634
Crit Rev Eukaryot Gene Expr. 2000;10(2):159-78
11186331
Hybridoma (Larchmt). 2007 Feb;26(1):22-7
17316082
Microb Pathog. 2005 Feb-Mar;38(2-3):97-105
15748811
Eur J Cancer. 2001 Jan;37(1):106-13
11165137
J Clin Invest. 2000 Jan;105(2):143-50
10642592
Neoplasia. 2001 Nov-Dec;3(6):459-68
11774028
Cancer Res. 2008 Aug 1;68(15):6251-9
18676849
J Natl Cancer Inst. 1997 Sep 3;89(17):1260-70
9293916
Cancer Cell. 2005 May;7(5):485-96
15894268
FASEB J. 2003 Sep;17(12):1751-3
12958198
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19327-32
18042722
Clin Exp Metastasis. 2006;23(7-8):335-44
17136575
Histol Histopathol. 1999 Apr;14(2):635-47
10212824
Nat Rev Cancer. 2002 Aug;2(8):584-93
12154351
J Natl Cancer Inst. 2002 Jan 2;94(1):17-25
11773278
Cancer Res. 1992 Mar 15;52(6):1399-405
1540948
Br J Cancer. 1987 Jan;55(1):61-6
3814476
Curr Biol. 1999 Dec 16-30;9(24):1441-7
10607586
Cancer Res. 2004 Jan 15;64(2):665-71
14744783
Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13453-8
9811821
J Biol Chem. 2001 Jul 27;276(30):28261-7
11375993