title: Lactoferricin enhances BMP7-stimulated anabolic pathways in intervertebral disc cells.
abstract: Bone-morphogenetic protein-7 (BMP7) is a well-known anabolic and anti-catabolic growth factor on intervertebral disc (IVD) matrix and cell homeostasis. Similarly, Lactoferricin B (LfcinB) has recently been shown to have pro-anabolic, anti-catabolic, anti-oxidative and/or anti-inflammatory effects in bovine disc cells in vitro. In this study, we investigated the potential benefits of using combined peptide therapy with LfcinB and BMP7 for intervertebral disc matrix repair and to understand cellular and signaling mechanisms controlled by these factors. We studied the effects of BMP7 and LfcinB as individual treatments and combined therapy on bovine nucleus pulposus (NP) cells by assessing proteoglycan (PG) accumulation and synthesis, and the gene expression of matrix protein aggrecan and transcription factor SOX-9. We also analyzed the role of Noggin, a BMP antagonist, in IVD tissue and examined its effect after stimulation with LfcinB. To understand the molecular mechanisms by which LfcinB synergizes with BMP7, we investigated the ERK-SP1 axis as a downstream intracellular signaling regulator involved in BMP7 and LfcinB-mediated activities. Treatment of bovine NP cells cultured in alginate with LfcinB plus BMP7 synergistically stimulates PG synthesis and accumulation in part by upregulation of aggrecan gene expression. The synergism results from LfcinB-mediated activation of Sp1 and SMAD signaling pathways by (i) phosphorylation of SMAD 1/5/8; (ii) downregulation of SMAD inhibitory factors [i.e., noggin and SMAD6 (inhibitory SMAD)]; and (iii) upregulation of SMAD4 (universal co-SMAD). These data indicate that LfcinB-suppression of Noggin may eliminate the negative feedback of BMP7, thereby maximizing biological activity of BMP7 and ultimately shifting homeostasis to a pro-anabolic state in disc cells. We propose that combination growth factor therapy using BMP7 and LfcinB may be beneficial for treatment of disc degeneration.
authors: Department of Biochemistry, Section of Rheumatology, Rush University Medical Center, Chicago, IL 60612, USA.
authors: Michael B
authors: MB
authors: Ellman
authors: Jaesung
authors: J
authors: Kim
authors: Howard S
authors: HS
authors: An
authors: Di
authors: D
authors: Chen
authors: Ranjan
authors: R
authors: Kc
authors: Xin
authors: X
authors: Li
authors: Guozhi
authors: G
authors: Xiao
authors: Dongyao
authors: D
authors: Yan
authors: Joon
authors: J
authors: Suh
authors: Andre J
authors: AJ
authors: van Wijnen
authors: James H-C
authors: JH
authors: Wang
authors: Su-Gwan
authors: SG
authors: Kim
authors: Hee-Jeong
authors: HJ
authors: Im
mesh_terms: D053674:Aggrecans / Q000235:genetics / Q000378:metabolism; D000464:Alginates / Q000494:pharmacology; D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002417:Cattle; D002452:Cell Count; D002478:Cells, Cultured; D024043:Collagen Type II / Q000378:metabolism; D004357:Drug Synergism; D020723:Glucuronic Acid / Q000494:pharmacology; D006603:Hexuronic Acids / Q000494:pharmacology; D006706:Homeostasis; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007403:Intervertebral Disc / Q000187:drug effects* / Q000378:metabolism; D007781:Lactoferrin / Q000494:pharmacology*; D010766:Phosphorylation; D011509:Proteoglycans / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051905:Smad6 Protein / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D053674:Aggrecans; D000464:Alginates; D055419:Bone Morphogenetic Protein 7; D002352:Carrier Proteins; D024043:Collagen Type II; D020723:Glucuronic Acid; D006603:Hexuronic Acids; D007334:Insulin-Like Growth Factor I; D007781:Lactoferrin; D011509:Proteoglycans; D055758:SOX9 Transcription Factor; D051905:Smad6 Protein; D000099176:Noggin Protein; C082171:lactoferricin B
references: Arthritis Rheum. 1996 Nov;39(11):1896-904
references: 8912513
references: Arthritis Rheum. 2010 Dec;62(12):3706-15
references: 20812336
references: Biochem Biophys Res Commun. 2008 May 2;369(2):679-85
references: 18307974
references: Lancet. 1999 Aug 14;354(9178):581-5
references: 10470716
references: Arthritis Rheum. 2005 Dec;52(12):3910-7
references: 16320338
references: Arthritis Res Ther. 2007;9(4):R77
references: 17688691
references: J Orthop Res. 2003 Sep;21(5):922-30
references: 12919882
references: Exp Cell Res. 2007 Jul 15;313(12):2634-50
references: 17570361
references: Spine (Phila Pa 1976). 2007 May 15;32(11):1197-205
references: 17495776
references: PLoS One. 2011;6(7):e22819
references: 21829524
references: Spine (Phila Pa 1976). 2008 Nov 15;33(24):2586-95
references: 19011540
references: Spine J. 2006 Nov-Dec;6(6):692-703
references: 17088200
references: Spine J. 2005 May-Jun;5(3):231-8
references: 15863076
references: Spine (Phila Pa 1976). 1988 Nov;13(11):1284-90
references: 3264623
references: J Cell Biol. 1993 Feb;120(3):825-34
references: 7678838
references: Biochim Biophys Acta. 2008 Sep;1783(9):1605-12
references: 18471442
references: Arthritis Rheum. 2003 Aug;48(8):2188-96
references: 12905472
references: Biomed Pharmacother. 2006 Dec;60(10):639-43
references: 17056223
references: Biomaterials. 2006 Jan;27(3):371-6
references: 16098581
references: Gene. 2013 Mar 15;517(1):12-8
references: 23313877
references: Spine (Phila Pa 1976). 2003 Aug 1;28(15 Suppl):S86-92
references: 12897480
references: Expert Rev Mol Med. 2001 Mar 29;2001:1-10
references: 14987359
references: J Biol Chem. 2007 Oct 26;282(43):31409-21
references: 17724016
references: Eur Spine J. 2008 Dec;17 Suppl 4:441-51
references: 19005698
references: J Bone Miner Res. 2006 Jul;21(7):1022-33
references: 16813523
references: Spine (Phila Pa 1976). 2005 Jan 1;30(1):25-31; discussion 31-2
references: 15626976
references: Spine (Phila Pa 1976). 2003 Aug 1;28(15 Suppl):S24-5
references: 12897470
references: Gene. 2008 Aug 15;420(1):82-9
references: 18565695
references: Mol Cell Biol. 2005 Nov;25(22):9845-58
references: 16260601
references: Nat Genet. 1999 May;22(1):85-9
references: 10319868
references: Spine (Phila Pa 1976). 2006 Apr 1;31(7):742-54
references: 16582847
references: Biochem Soc Trans. 2007 Aug;35(Pt 4):652-5
references: 17635113
references: J Biol Chem. 2004 Feb 20;279(8):6737-45
references: 14660675
references: Arthritis Rheum. 2000 Sep;43(9):2110-20
references: 11014363
references: Spine (Phila Pa 1976). 2004 Dec 1;29(23):2691-9
references: 15564918
references: Spine (Phila Pa 1976). 2002 Jun 15;27(12):1318-25
references: 12065981
references: J Biol Chem. 2007 Apr 13;282(15):11110-21
references: 17311929
references: Aging Clin Exp Res. 2003 Oct;15(5):364-72
references: 14703002
references: J Pathol. 2004 Sep;204(1):47-54
references: 15307137
references: J Cell Physiol. 2013 Sep;228(9):1884-96
references: 23460134
references: Arthritis Res Ther. 2008;10(2):R48
references: 18435858
references: J Cell Physiol. 2012 Apr;227(4):1512-20
references: 21678402
references: Spine (Phila Pa 1976). 2005 Sep 1;30(17):1940-8
references: 16135983
references: Comp Biochem Physiol C Toxicol Pharmacol. 2004 Oct;139(1-3):65-75
references: 15556067
references: J Biol Chem. 1992 Oct 5;267(28):20352-62
references: 1328198
references: Spine (Phila Pa 1976). 2004 Dec 1;29(23):2757-69
references: 15564925
references: Biochem Cell Biol. 2002;80(1):131-6
references: 11908637
references: Pharm Res. 2008 Oct;25(10):2440-6
references: 18288447
references: J Biol Chem. 2003 Jul 11;278(28):25386-94
references: 12734180
references: J Vet Med Sci. 2004 Feb;66(2):149-54
references: 15031542
references: J Biol Chem. 1992 Mar 25;267(9):6093-8
references: 1556117
references: Am J Pathol. 2006 Nov;169(5):1753-66
references: 17071598
references: J Cell Physiol. 2006 Dec;209(3):744-54
references: 16955489
references: Cell Mol Life Sci. 2005 Nov;62(22):2588-98
references: 16261252
references: Am J Phys Med Rehabil. 2004 Jul;83(7):515-21
references: 15213475
references: Arthritis Rheum. 2000 Sep;43(9):2073-80
references: 11014359