title: F-spondin, a neuroregulatory protein, is up-regulated in osteoarthritis and regulates cartilage metabolism via TGF-beta activation.
abstract: In osteoarthritis (OA) articular chondrocytes undergo phenotypic changes culminating in the progressive loss of cartilage from the joint surface. The molecular mechanisms underlying these changes are poorly understood. Here we report enhanced (approximately 7-fold) expression of F-spondin, a neuronal extracellular matrix glycoprotein, in human OA cartilage (P<0.005). OA-specific up-regulation of F-spondin was also demonstrated in rat knee cartilage following surgical menisectomy. F-spondin treatment of OA cartilage explants caused a 2-fold increase in levels of the active form of TGF-beta1 (P<0.01) and a 10-fold induction of PGE2 (P<0.005) in culture supernatants. PGE2 induction was found to be dependent on TGF-beta and the thrombospondin domain of the F-spondin molecule. F-spondin addition to cartilage explant cultures also caused a 4-fold increase in collagen degradation (P<0.05) and a modest reduction in proteoglycan synthesis (approximately 20%; P<0.05), which were both TGF-beta and PGE2 dependent. F-spondin treatment also led to increased secretion and activation of MMP-13 (P<0.05). Together these studies identify F-spondin as a novel protein in OA cartilage, where it may act in situ at lesional areas to activate latent TGF-beta and induce cartilage degradation via pathways that involve production of PGE2.
authors.affiliation: Division of Rheumatology, New York University School of Medicine, New York University Hospital for Joint Diseases, 301 E. 17th St., New York, NY 10003, USA.
authors.forename: Mukundan G
authors.initials: MG
authors.lastname: Attur
authors.forename: Glyn D
authors.initials: GD
authors.lastname: Palmer
authors.forename: Hayf E
authors.initials: HE
authors.lastname: Al-Mussawir
authors.forename: Mandar
authors.initials: M
authors.lastname: Dave
authors.forename: Cristina C
authors.initials: CC
authors.lastname: Teixeira
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rifkin
authors.forename: C Thomas G
authors.initials: CT
authors.lastname: Appleton
authors.forename: Frank
authors.initials: F
authors.lastname: Beier
authors.forename: Steven B
authors.initials: SB
authors.lastname: Abramson
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010003:Osteoarthritis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016326:Extracellular Matrix Proteins; C429104:SPON1 protein, human; D016212:Transforming Growth Factor beta
references.citation: Br J Rheumatol. 1993 Apr;32(4):281-6
references.pmid: 8461920
references.citation: J Clin Invest. 1977 Apr;59(4):593-600
references.pmid: 845251
references.citation: Curr Drug Targets. 2007 Feb;8(2):377-85
references.pmid: 17305515
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4722-7
references.pmid: 11287656
references.citation: J Clin Invest. 1997 Mar 15;99(6):1231-7
references.pmid: 9077531
references.citation: Arthritis Res Ther. 2003;5(3):R132-9
references.pmid: 12723985
references.citation: J Cell Biol. 2002 Jan 21;156(2):227-32
references.pmid: 11790802
references.citation: Osteoarthritis Cartilage. 2007 Jun;15(6):597-604
references.pmid: 17391995
references.citation: Osteoarthritis Cartilage. 2000 Jan;8(1):25-33
references.pmid: 10607496
references.citation: J Rheumatol. 2005 May;32(5):876-86
references.pmid: 15868625
references.citation: Clin Orthop Relat Res. 2000 Aug;(377):119-25
references.pmid: 10943193
references.citation: Neuron. 1999 Jun;23(2):233-46
references.pmid: 10399931
references.citation: Rheumatol Int. 2005 Mar;25(2):118-24
references.pmid: 14618374
references.citation: Am J Pathol. 2006 Jan;168(1):131-40
references.pmid: 16400016
references.citation: Cell. 1992 Apr 3;69(1):95-110
references.pmid: 1555244
references.citation: Front Biosci. 1999 Oct 15;4:D694-703
references.pmid: 10525480
references.citation: J Exp Med. 1995 Dec 1;182(6):2097-102
references.pmid: 7500055
references.citation: J Cell Physiol. 2007 Dec;213(3):626-34
references.pmid: 17786965
references.citation: J Biol Chem. 1999 May 7;274(19):13586-93
references.pmid: 10224129
references.citation: Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):59-69
references.pmid: 10708953
references.citation: Arthritis Rheum. 2006 May;54(5):1357-60
references.pmid: 16645963
references.citation: Arthritis Res. 2001;3(2):107-13
references.pmid: 11178118
references.citation: Clin Orthop Relat Res. 2004 Oct;(427 Suppl):S27-36
references.pmid: 15480070
references.citation: Arthritis Res Ther. 2007;9(1):R13
references.pmid: 17284317
references.citation: J Cell Biol. 2001 Apr 2;153(1):35-46
references.pmid: 11285272
references.citation: J Rheumatol. 2001 Jul;28(7):1631-9
references.pmid: 11469472
references.citation: Arthritis Rheum. 2001 Mar;44(3):578-84
references.pmid: 11263772
references.citation: J Cell Physiol. 2005 Aug;204(2):560-6
references.pmid: 15799031
references.citation: J Orthop Sci. 2003;8(3):294-300
references.pmid: 12768468
references.citation: Anal Biochem. 1994 Feb 1;216(2):276-84
references.pmid: 8179182
references.citation: Curr Issues Mol Biol. 2002 Oct;4(4):129-46
references.pmid: 12432964
references.citation: Mol Endocrinol. 1996 Sep;10(9):1077-83
references.pmid: 8885242
references.citation: J Biol Chem. 2007 Mar 30;282(13):9492-9504
references.pmid: 17283078
references.citation: Neuron. 1999 Mar;22(3):475-88
references.pmid: 10197528
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: J Cell Biol. 1990 Apr;110(4):1361-7
references.pmid: 2139036
references.citation: J Cell Biol. 1997 Oct 20;139(2):541-52
references.pmid: 9334355
references.citation: J Immunol. 2008 Oct 1;181(7):5082-8
references.pmid: 18802112
references.citation: Arthritis Rheum. 1999 Jul;42(7):1443-50
references.pmid: 10403272