title: Fibroblast growth factor-1 is a mesenchymal stromal cell-secreted factor stimulating proliferation of osteoarthritic chondrocytes in co-culture.
abstract: Previously, we showed that mesenchymal stromal cells (MSCs) in co-culture with primary chondrocytes secrete soluble factors that increase chondrocyte proliferation. The objective of this study is to identify these factors. Human primary chondrocytes (hPCs) isolated from late-stage osteoarthritis patients were co-cultured with human bone marrow-derived MSCs (hMSCs) in pellets. Genome-wide mRNA expression analysis and quantitative polymerase chain reactions (qPCR) were used to identify soluble factors that were specifically induced in co-cultures. Immunofluorescent staining combined with cell tracking and enzyme-linked immunosorbent assay (ELISA) were performed to validate up-regulation at the protein level and to identify the cellular origin of the increased proteins. Chemical blockers and neutralizing antibodies were used to elucidate the role of the identified candidate genes in co-cultures. A number of candidate factors were differentially regulated in co-cultures at the mRNA level. Of these, fibroblast growth factor-1 (FGF-1) mRNA and protein expression were markedly increased in co-cultures predominantly due to up-regulated expression in MSCs. Blocking of FGF signaling in co-culture pellets by specific FGF receptor inhibitors or FGF-1 neutralizing antibodies completely blocked hPCs proliferation. We demonstrate that MSCs increase FGF-1 secretion on co-culture with hPCs, which, in turn, is responsible for increased hPCs proliferation in pellet co-cultures.
authors.affiliation: Department of Developmental BioEngineering, University of Twente , Enschede, The Netherlands.
authors.forename: Ling
authors.initials: L
authors.lastname: Wu
authors.forename: Jeroen
authors.initials: J
authors.lastname: Leijten
authors.forename: Clemens A
authors.initials: CA
authors.lastname: van Blitterswijk
authors.forename: Marcel
authors.initials: M
authors.lastname: Karperien
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology; D001854:Bone Marrow Cells / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D018920:Coculture Techniques; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D015854:Up-Regulation
chemical_list: D057134:Antibodies, Neutralizing; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D016220:Fibroblast Growth Factor 1
references.citation: J Med Assoc Thai. 2011 Mar;94(3):395-400
references.pmid: 21560849
references.citation: Trends Genet. 2004 Nov;20(11):563-9
references.pmid: 15475116
references.citation: J Cell Mol Med. 2010 Apr;14(4):922-32
references.pmid: 19243475
references.citation: BMC Mol Biol. 2008 Feb 26;9:26
references.pmid: 18302751
references.citation: Arthritis Rheum. 2009 Apr;60(4):1006-19
references.pmid: 19333946
references.citation: Histochem Cell Biol. 2008 Feb;129(2):203-10
references.pmid: 17978832
references.citation: Arthritis Rheum. 2011 Nov;63(11):3417-27
references.pmid: 21769844
references.citation: Cell Transplant. 2011;20(9):1381-93
references.pmid: 21176404
references.citation: Mol Ther. 2012 Jan;20(1):14-20
references.pmid: 22008910
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D561-8
references.pmid: 21045058
references.citation: Am J Sports Med. 2005 Feb;33(2):295-306
references.pmid: 15701618
references.citation: Arthritis Rheum. 2007 Mar;56(3):714-21
references.pmid: 17328041
references.citation: Mol Med Rep. 2011 Jul-Aug;4(4):621-6
references.pmid: 21503577
references.citation: Am J Sports Med. 2005 Mar;33(3):443-60
references.pmid: 15716263
references.citation: Osteoarthritis Cartilage. 2002 Mar;10(3):199-206
references.pmid: 11869080
references.citation: Eur Cell Mater. 2012 Jun 05;23:387-99
references.pmid: 22665161
references.citation: J Proteome Res. 2010 Jun 4;9(6):2946-56
references.pmid: 20359165
references.citation: Endocrinology. 2011 Nov;152(11):4232-41
references.pmid: 21914781
references.citation: Mol Cell Proteomics. 2010 Mar;9(3):550-64
references.pmid: 20008835
references.citation: Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10691-5
references.pmid: 1279690
references.citation: Arthritis Rheum. 2007 Apr;56(4):1175-86
references.pmid: 17393437
references.citation: Proc Soc Exp Biol Med. 1992 Jun;200(2):165-70
references.pmid: 1374563
references.citation: Arthritis Res Ther. 2009;11(5):R148
references.pmid: 19799789
references.citation: Arthritis Rheum. 2012 Nov;64(11):3604-13
references.pmid: 22961401
references.citation: Arthritis Rheum. 2011 Sep;63(9):2547-57
references.pmid: 21647863
references.citation: FASEB J. 1995 Jul;9(10):919-25
references.pmid: 7542215
references.citation: Arthritis Rheum. 2012 Oct;64(10):3302-12
references.pmid: 22576962
references.citation: Tissue Eng Part A. 2012 Aug;18(15-16):1542-51
references.pmid: 22429306
references.citation: PLoS One. 2011;6(7):e22887
references.pmid: 21818404
references.citation: J Cell Biochem. 2003 Dec 15;90(6):1112-27
references.pmid: 14635186
references.citation: Exp Cell Res. 2010 Apr 15;316(7):1271-81
references.pmid: 20206158
references.citation: Tissue Eng Part A. 2011 May;17(9-10):1425-36
references.pmid: 21247341
references.citation: Differentiation. 2001 Jun;67(4-5):128-38
references.pmid: 11683496
references.citation: Stem Cells Dev. 2010 Jun;19(6):887-902
references.pmid: 19686050
references.citation: Cytokine Growth Factor Rev. 2005 Apr;16(2):205-13
references.pmid: 15863035
references.citation: Arthritis Rheum. 2003 Dec;48(12):3464-74
references.pmid: 14673997
references.citation: Osteoarthritis Cartilage. 2007 Oct;15(10):1178-89
references.pmid: 17502159
references.citation: Arthritis Res Ther. 2011 Aug 11;13(4):R130
references.pmid: 21835001
references.citation: Stem Cells. 2008 Sep;26(9):2287-99
references.pmid: 18566331
references.citation: Nat Med. 2009 Jan;15(1):42-9
references.pmid: 19098906
references.citation: J Cell Physiol. 2012 Jan;227(1):88-97
references.pmid: 22025108
references.citation: Endocr Rev. 2005 Feb;26(1):63-77
references.pmid: 15689573
references.citation: Osteoarthritis Cartilage. 2010 Feb;18(2):208-19
references.pmid: 19748609
references.citation: Stem Cells Dev. 2013 Jun 1;22(11):1657-69
references.pmid: 23301843
references.citation: J Cell Biochem. 2006 Aug 1;98(5):1076-84
references.pmid: 16619257
references.citation: J Cell Sci. 2011 Oct 15;124(Pt 20):3428-40
references.pmid: 21984813
references.citation: J Biomed Mater Res A. 2007 Dec 1;83(3):626-35
references.pmid: 17503531
references.citation: Mol Cell Proteomics. 2007 Apr;6(4):589-600
references.pmid: 17255083