Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis.
Bone metastasis is a hallmark of advanced prostate and breast cancers, yet the critical factors behind attraction of tumors to the skeleton have not been validated. Here, we investigated the involvement of cathepsin K in the progression of prostate tumors in the bone, which occurs both by direct degradation of bone matrix collagen I and by cleavage of other factors in the bone microenvironment. Our results demonstrated that bone marrow-derived cathepsin K is capable of processing and thereby modulating SPARC, a protein implicated in bone metastasis and inflammation. The coincident up-regulation of SPARC and cathepsin K occurred both in vivo in experimental prostate bone tumors, and in vitro in co-cultures of bone marrow stromal cells with PC3 prostate carcinoma cells. PC3-bone marrow stromal cell interaction increased secretion and processing of SPARC, as did co-cultures of bone marrow stromal cells with two other cancer cell lines. In addition, bone marrow stromal cells that were either deficient in cathepsin K or treated with cathepsin K inhibitors had significantly reduced secretion and cleavage of SPARC. Increases in secretion of pro-inflammatory cytokines (ie, interleukin-6, -8) coincident with overexpression of cathepsin K suggest possible mechanisms by which this enzyme contributes to tumor progression in the bone. This is the first study implicating bone marrow cathepsin K in regulation of biological activity of SPARC in bone metastasis.
Podgorski
Izabela
I
Wayne State University School of Medicine, Department of Pharmacology, 540 E. Canfield, Detroit, MI 48201, USA. ipodgors@med.wayne.edu
Linebaugh
Bruce E
BE
Koblinski
Jennifer E
JE
Rudy
Deborah L
DL
Herroon
Mackenzie K
MK
Olive
Mary B
MB
Sloane
Bonnie F
BF
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary*; D056657:Cathepsin K / Q000096:biosynthesis*; D002450:Cell Communication; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D015676:Osteonectin / Q000096:biosynthesis*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
D015850:Interleukin-6; D016209:Interleukin-8; D015676:Osteonectin; D056657:Cathepsin K
Clin Cancer Res. 2006 Oct 15;12(20 Pt 2):6213s-6216s
17062703
Cancer Res. 2007 Oct 15;67(20):9894-902
17942921
J Natl Cancer Inst. 2002 Jan 2;94(1):17-25
11773278
Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13453-8
9811821
Urol Oncol. 2007 Sep-Oct;25(5):407-11
17826661
J Bone Miner Res. 2003 Feb;18(2):222-30
12568399
Cancer Res. 1998 Apr 1;58(7):1395-9
9537238
J Rheumatol. 1999 Apr;26(4):791-9
10229398
J Cell Biochem. 2009 Mar 1;106(4):563-9
19170075
Oncol Res. 1996;8(2):63-7
8859776
Biomed Pharmacother. 2008 Feb;62(2):130-5
17728092
Histol Histopathol. 2004 Jan;19(1):189-99
14702187
Br J Cancer. 2000 Feb;82(4):858-64
10732759
Matrix Biol. 2001 Jan;19(8):816-27
11223341
J Bone Miner Res. 2001 Aug;16(8):1444-52
11499867
Bioorg Med Chem Lett. 2006 Apr 1;16(7):1985-9
16413777
J Biol Chem. 1996 May 24;271(21):12517-24
8647860
Cancer Res. 2006 Aug 15;66(16):7968-75
16912171
Int J Biochem Cell Biol. 2008;40(6-7):1185-98
18243768
Cancer Res. 2005 Jun 15;65(12):5123-32
15958556
Nutr Rev. 2007 Dec;65(12 Pt 2):S147-51
18240539
Cancer Res. 2005 Aug 15;65(16):7370-7
16103089
Science. 2008 Feb 1;319(5863):624-7
18239127
J Cell Physiol. 2003 Jan;194(1):71-9
12447991
Cancer Cell. 2004 Jul;6(1):17-32
15261139
J Rheumatol. 1998 Oct;25(10):1887-94
9779840
Biochimie. 2008 Feb;90(2):208-26
17935853
J Clin Invest. 2000 May;105(9):1325
10792008
Prostate. 2006 Sep 1;66(12):1311-8
16705739
Nat Rev Cancer. 2006 Oct;6(10):764-75
16990854
Anal Chem. 2005 Nov 1;77(21):6765-71
16255572
Cell. 2006 Jan 27;124(2):263-6
16439202
Cancer Res. 2007 Mar 15;67(6):2649-56
17363585
Int J Biochem Cell Biol. 1999 Dec;31(12):1363-6
10641790
Am J Clin Pathol. 2006 Jun;125(6):847-54
16690483
J Biol Chem. 2005 Aug 5;280(31):28370-81
15929988
J Cell Physiol. 1997 Dec;173(3):327-34
9369945
Biochem Soc Trans. 2007 Aug;35(Pt 4):701-3
17635127
J Biol Chem. 1997 Apr 4;272(14):9237-43
9083057
Invest Urol. 1979 Jul;17(1):16-23
447482
Drug Resist Updat. 2008 Dec;11(6):231-46
18849185
J Pathol. 2002 Mar;196(3):254-65
11857487
Cancer Res. 1999 Apr 15;59(8):1987-93
10213511
Endocrinology. 2005 Apr;146(4):1727-36
15637291
J Cell Biochem. 2004 Jul 1;92(4):679-90
15211566
Mol Carcinog. 2001 Oct;32(2):84-91
11746820
Biochim Biophys Acta. 2008 Apr;1785(2):85-95
18082147
Genomics. 1997 Apr 15;41(2):169-76
9143491
Int J Cancer. 1978 Mar 15;21(3):274-81
631930
Neurosci Lett. 2007 May 29;419(2):172-7
17490812
Clin Cancer Res. 2008 Sep 1;14(17):5357-67
18765527
Cancer Res. 1997 Dec 1;57(23):5386-90
9393764
Histochem Cell Biol. 2003 Nov;120(5):391-400
14600836
N Engl J Med. 2009 Feb 12;360(7):679-91
19213681
J Exp Med. 2000 Sep 18;192(6):789-99
10993910
J Biol Chem. 1998 Nov 27;273(48):32347-52
9822715
Anal Biochem. 1983 Jun;131(2):538-47
6193739
Clin Sci (Lond). 2007 Jun;112(11):567-75
17241109
Med Oncol. 2009;26(1):10-5
18461289
Cancer Metastasis Rev. 2008 Sep;27(3):523-37
18459035
J Clin Invest. 1999 Mar;103(5):731-8
10074491
Arthritis Rheum. 1999 Aug;42(8):1588-93
10446855
J Biol Chem. 2003 Sep 26;278(39):37849-57
12867428
Autoimmunity. 2008 Apr;41(3):183-94
18365831
J Biol Chem. 2003 Oct 3;278(40):39044-50
12885781
Cancer Biol Ther. 2007 Apr;6(4):618-9
18027438
Prostate. 2000 Jul 1;44(2):91-103 Jul 1;44(2)
10881018
Cancer Res. 1998 May 15;58(10):2209-16
9605768
Nat Med. 2006 Jun;12(6):657-64
16715089
J Immunol. 2006 May 15;176(10):5825-32
16670288
J Clin Invest. 1994 Sep;94(3):1012-8
8083342
J Cell Biochem. 2008 Jun 1;104(3):721-32
18253934
Clin Cancer Res. 2000 Mar;6(3):1140-9
10741745
J Bone Miner Res. 2001 Aug;16(8):1486-95
11499871
Gene. 2007 Nov 15;403(1-2):151-8
17897792
Cancer Res. 1999 Sep 1;59(17):4453-7
10485497
Neoplasia. 2005 Mar;7(3):207-23
15799821
J Cell Biol. 1994 May;125(4):929-43
7514608
Cancer Res. 2007 Apr 15;67(8):3646-53
17440076
Biochem J. 1998 May 1;331 ( Pt 3):727-32
9560298
Cancer Metastasis Rev. 2008 Mar;27(1):41-55
18071636
Cancer Res. 2001 Jan 15;61(2):532-7
11212246
Cancer Res. 2008 Nov 1;68(21):9050-9
18974151
Science. 1996 Aug 30;273(5279):1236-8
8703060
Bone. 2005 Jan;36(1):159-72
15664014