F-spondin, a neuroregulatory protein, is up-regulated in osteoarthritis and regulates cartilage metabolism via TGF-beta activation.
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.
Attur
Mukundan G
MG
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.
Palmer
Glyn D
GD
Al-Mussawir
Hayf E
HE
Dave
Mandar
M
Teixeira
Cristina C
CC
Rifkin
Daniel B
DB
Appleton
C Thomas G
CT
Beier
Frank
F
Abramson
Steven B
SB
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
D016326:Extracellular Matrix Proteins; C429104:SPON1 protein, human; D016212:Transforming Growth Factor beta
Br J Rheumatol. 1993 Apr;32(4):281-6
8461920
J Clin Invest. 1977 Apr;59(4):593-600
845251
Curr Drug Targets. 2007 Feb;8(2):377-85
17305515
Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4722-7
11287656
J Clin Invest. 1997 Mar 15;99(6):1231-7
9077531
Arthritis Res Ther. 2003;5(3):R132-9
12723985
J Cell Biol. 2002 Jan 21;156(2):227-32
11790802
Osteoarthritis Cartilage. 2007 Jun;15(6):597-604
17391995
Osteoarthritis Cartilage. 2000 Jan;8(1):25-33
10607496
J Rheumatol. 2005 May;32(5):876-86
15868625
Clin Orthop Relat Res. 2000 Aug;(377):119-25
10943193
Neuron. 1999 Jun;23(2):233-46
10399931
Rheumatol Int. 2005 Mar;25(2):118-24
14618374
Am J Pathol. 2006 Jan;168(1):131-40
16400016
Cell. 1992 Apr 3;69(1):95-110
1555244
Front Biosci. 1999 Oct 15;4:D694-703
10525480
J Exp Med. 1995 Dec 1;182(6):2097-102
7500055
J Cell Physiol. 2007 Dec;213(3):626-34
17786965
J Biol Chem. 1999 May 7;274(19):13586-93
10224129
Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):59-69
10708953
Arthritis Rheum. 2006 May;54(5):1357-60
16645963
Arthritis Res. 2001;3(2):107-13
11178118
Clin Orthop Relat Res. 2004 Oct;(427 Suppl):S27-36
15480070
Arthritis Res Ther. 2007;9(1):R13
17284317
J Cell Biol. 2001 Apr 2;153(1):35-46
11285272
J Rheumatol. 2001 Jul;28(7):1631-9
11469472
Arthritis Rheum. 2001 Mar;44(3):578-84
11263772
J Cell Physiol. 2005 Aug;204(2):560-6
15799031
J Orthop Sci. 2003;8(3):294-300
12768468
Anal Biochem. 1994 Feb 1;216(2):276-84
8179182
Curr Issues Mol Biol. 2002 Oct;4(4):129-46
12432964
Mol Endocrinol. 1996 Sep;10(9):1077-83
8885242
J Biol Chem. 2007 Mar 30;282(13):9492-9504
17283078
Neuron. 1999 Mar;22(3):475-88
10197528
Methods. 2001 Dec;25(4):402-8
11846609
J Cell Biol. 1990 Apr;110(4):1361-7
2139036
J Cell Biol. 1997 Oct 20;139(2):541-52
9334355
J Immunol. 2008 Oct 1;181(7):5082-8
18802112
Arthritis Rheum. 1999 Jul;42(7):1443-50
10403272