title: Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis.
abstract: 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.
authors.affiliation: Wayne State University School of Medicine, Department of Pharmacology, 540 E. Canfield, Detroit, MI 48201, USA. ipodgors@med.wayne.edu
authors.forename: Izabela
authors.initials: I
authors.lastname: Podgorski
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Linebaugh
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Koblinski
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Rudy
authors.forename: Mackenzie K
authors.initials: MK
authors.lastname: Herroon
authors.forename: Mary B
authors.initials: MB
authors.lastname: Olive
authors.forename: Bonnie F
authors.initials: BF
authors.lastname: Sloane
mesh_terms: 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
chemical_list: D015850:Interleukin-6; D016209:Interleukin-8; D015676:Osteonectin; D056657:Cathepsin K
references.citation: Clin Cancer Res. 2006 Oct 15;12(20 Pt 2):6213s-6216s
references.pmid: 17062703
references.citation: Cancer Res. 2007 Oct 15;67(20):9894-902
references.pmid: 17942921
references.citation: J Natl Cancer Inst. 2002 Jan 2;94(1):17-25
references.pmid: 11773278
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13453-8
references.pmid: 9811821
references.citation: Urol Oncol. 2007 Sep-Oct;25(5):407-11
references.pmid: 17826661
references.citation: J Bone Miner Res. 2003 Feb;18(2):222-30
references.pmid: 12568399
references.citation: Cancer Res. 1998 Apr 1;58(7):1395-9
references.pmid: 9537238
references.citation: J Rheumatol. 1999 Apr;26(4):791-9
references.pmid: 10229398
references.citation: J Cell Biochem. 2009 Mar 1;106(4):563-9
references.pmid: 19170075
references.citation: Oncol Res. 1996;8(2):63-7
references.pmid: 8859776
references.citation: Biomed Pharmacother. 2008 Feb;62(2):130-5
references.pmid: 17728092
references.citation: Histol Histopathol. 2004 Jan;19(1):189-99
references.pmid: 14702187
references.citation: Br J Cancer. 2000 Feb;82(4):858-64
references.pmid: 10732759
references.citation: Matrix Biol. 2001 Jan;19(8):816-27
references.pmid: 11223341
references.citation: J Bone Miner Res. 2001 Aug;16(8):1444-52
references.pmid: 11499867
references.citation: Bioorg Med Chem Lett. 2006 Apr 1;16(7):1985-9
references.pmid: 16413777
references.citation: J Biol Chem. 1996 May 24;271(21):12517-24
references.pmid: 8647860
references.citation: Cancer Res. 2006 Aug 15;66(16):7968-75
references.pmid: 16912171
references.citation: Int J Biochem Cell Biol. 2008;40(6-7):1185-98
references.pmid: 18243768
references.citation: Cancer Res. 2005 Jun 15;65(12):5123-32
references.pmid: 15958556
references.citation: Nutr Rev. 2007 Dec;65(12 Pt 2):S147-51
references.pmid: 18240539
references.citation: Cancer Res. 2005 Aug 15;65(16):7370-7
references.pmid: 16103089
references.citation: Science. 2008 Feb 1;319(5863):624-7
references.pmid: 18239127
references.citation: J Cell Physiol. 2003 Jan;194(1):71-9
references.pmid: 12447991
references.citation: Cancer Cell. 2004 Jul;6(1):17-32
references.pmid: 15261139
references.citation: J Rheumatol. 1998 Oct;25(10):1887-94
references.pmid: 9779840
references.citation: Biochimie. 2008 Feb;90(2):208-26
references.pmid: 17935853
references.citation: J Clin Invest. 2000 May;105(9):1325
references.pmid: 10792008
references.citation: Prostate. 2006 Sep 1;66(12):1311-8
references.pmid: 16705739
references.citation: Nat Rev Cancer. 2006 Oct;6(10):764-75
references.pmid: 16990854
references.citation: Anal Chem. 2005 Nov 1;77(21):6765-71
references.pmid: 16255572
references.citation: Cell. 2006 Jan 27;124(2):263-6
references.pmid: 16439202
references.citation: Cancer Res. 2007 Mar 15;67(6):2649-56
references.pmid: 17363585
references.citation: Int J Biochem Cell Biol. 1999 Dec;31(12):1363-6
references.pmid: 10641790
references.citation: Am J Clin Pathol. 2006 Jun;125(6):847-54
references.pmid: 16690483
references.citation: J Biol Chem. 2005 Aug 5;280(31):28370-81
references.pmid: 15929988
references.citation: J Cell Physiol. 1997 Dec;173(3):327-34
references.pmid: 9369945
references.citation: Biochem Soc Trans. 2007 Aug;35(Pt 4):701-3
references.pmid: 17635127
references.citation: J Biol Chem. 1997 Apr 4;272(14):9237-43
references.pmid: 9083057
references.citation: Invest Urol. 1979 Jul;17(1):16-23
references.pmid: 447482
references.citation: Drug Resist Updat. 2008 Dec;11(6):231-46
references.pmid: 18849185
references.citation: J Pathol. 2002 Mar;196(3):254-65
references.pmid: 11857487
references.citation: Cancer Res. 1999 Apr 15;59(8):1987-93
references.pmid: 10213511
references.citation: Endocrinology. 2005 Apr;146(4):1727-36
references.pmid: 15637291
references.citation: J Cell Biochem. 2004 Jul 1;92(4):679-90
references.pmid: 15211566
references.citation: Mol Carcinog. 2001 Oct;32(2):84-91
references.pmid: 11746820
references.citation: Biochim Biophys Acta. 2008 Apr;1785(2):85-95
references.pmid: 18082147
references.citation: Genomics. 1997 Apr 15;41(2):169-76
references.pmid: 9143491
references.citation: Int J Cancer. 1978 Mar 15;21(3):274-81
references.pmid: 631930
references.citation: Neurosci Lett. 2007 May 29;419(2):172-7
references.pmid: 17490812
references.citation: Clin Cancer Res. 2008 Sep 1;14(17):5357-67
references.pmid: 18765527
references.citation: Cancer Res. 1997 Dec 1;57(23):5386-90
references.pmid: 9393764
references.citation: Histochem Cell Biol. 2003 Nov;120(5):391-400
references.pmid: 14600836
references.citation: N Engl J Med. 2009 Feb 12;360(7):679-91
references.pmid: 19213681
references.citation: J Exp Med. 2000 Sep 18;192(6):789-99
references.pmid: 10993910
references.citation: J Biol Chem. 1998 Nov 27;273(48):32347-52
references.pmid: 9822715
references.citation: Anal Biochem. 1983 Jun;131(2):538-47
references.pmid: 6193739
references.citation: Clin Sci (Lond). 2007 Jun;112(11):567-75
references.pmid: 17241109
references.citation: Med Oncol. 2009;26(1):10-5
references.pmid: 18461289
references.citation: Cancer Metastasis Rev. 2008 Sep;27(3):523-37
references.pmid: 18459035
references.citation: J Clin Invest. 1999 Mar;103(5):731-8
references.pmid: 10074491
references.citation: Arthritis Rheum. 1999 Aug;42(8):1588-93
references.pmid: 10446855
references.citation: J Biol Chem. 2003 Sep 26;278(39):37849-57
references.pmid: 12867428
references.citation: Autoimmunity. 2008 Apr;41(3):183-94
references.pmid: 18365831
references.citation: J Biol Chem. 2003 Oct 3;278(40):39044-50
references.pmid: 12885781
references.citation: Cancer Biol Ther. 2007 Apr;6(4):618-9
references.pmid: 18027438
references.citation: Prostate. 2000 Jul 1;44(2):91-103 Jul 1;44(2)
references.pmid: 10881018
references.citation: Cancer Res. 1998 May 15;58(10):2209-16
references.pmid: 9605768
references.citation: Nat Med. 2006 Jun;12(6):657-64
references.pmid: 16715089
references.citation: J Immunol. 2006 May 15;176(10):5825-32
references.pmid: 16670288
references.citation: J Clin Invest. 1994 Sep;94(3):1012-8
references.pmid: 8083342
references.citation: J Cell Biochem. 2008 Jun 1;104(3):721-32
references.pmid: 18253934
references.citation: Clin Cancer Res. 2000 Mar;6(3):1140-9
references.pmid: 10741745
references.citation: J Bone Miner Res. 2001 Aug;16(8):1486-95
references.pmid: 11499871
references.citation: Gene. 2007 Nov 15;403(1-2):151-8
references.pmid: 17897792
references.citation: Cancer Res. 1999 Sep 1;59(17):4453-7
references.pmid: 10485497
references.citation: Neoplasia. 2005 Mar;7(3):207-23
references.pmid: 15799821
references.citation: J Cell Biol. 1994 May;125(4):929-43
references.pmid: 7514608
references.citation: Cancer Res. 2007 Apr 15;67(8):3646-53
references.pmid: 17440076
references.citation: Biochem J. 1998 May 1;331 ( Pt 3):727-32
references.pmid: 9560298
references.citation: Cancer Metastasis Rev. 2008 Mar;27(1):41-55
references.pmid: 18071636
references.citation: Cancer Res. 2001 Jan 15;61(2):532-7
references.pmid: 11212246
references.citation: Cancer Res. 2008 Nov 1;68(21):9050-9
references.pmid: 18974151
references.citation: Science. 1996 Aug 30;273(5279):1236-8
references.pmid: 8703060
references.citation: Bone. 2005 Jan;36(1):159-72
references.pmid: 15664014