title: Phosphocitrate is potentially a disease-modifying drug for noncrystal-associated osteoarthritis.
abstract: Phosphocitrate (PC), a calcification inhibitor, inhibits the development of crystal-associated osteoarthritis (OA) in Hartley guinea pigs. However, the molecular mechanisms underlying its disease-modifying effect remain elusive. This study sought to test the hypothesis that PC has calcium crystal-independent biological activities which are, at least in part, responsible for its disease-modifying activity. We found that PC inhibited the proliferation of OA fibroblast-like synoviocytes in the absence of calcium crystals. Consistent with its effect on cell proliferation, PC downregulated the expression of numerous genes classified in cell proliferation. PC also downregulated the expression of many genes classified in angiogenesis and inflammatory response including prostaglandin-endoperoxide synthase 2, interleukin-1 receptor, type I, and chemokine (C-C motif) ligand 2. In contrast, PC upregulated the expression of many genes classified in musculoskeletal tissue development, including aggrecan, type I collagen, and insulin-like growth factor binding protein 5. These findings suggest that PC is not only a promising disease-modifying drug for crystal-associated OA but also for noncrystal-associated OA.
authors.affiliation: Department of Orthopedic Surgery, Carolinas Medical Center, P.O. Box 32861, Charlotte, NC 28232, USA. yubo.sun@carolinas.org
authors.forename: Yubo
authors.initials: Y
authors.lastname: Sun
authors.forename: David R
authors.initials: DR
authors.lastname: Mauerhan
authors.forename: Atiya M
authors.initials: AM
authors.lastname: Franklin
authors.forename: James
authors.initials: J
authors.lastname: Norton
authors.forename: Edward N
authors.initials: EN
authors.lastname: Hanley
authors.forename: Helen E
authors.initials: HE
authors.lastname: Gruber
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage*; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002951:Citrates / Q000008:administration & dosage*; D015536:Down-Regulation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D010003:Osteoarthritis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013582:Synovial Fluid / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018501:Antirheumatic Agents; D002951:Citrates; C014148:phosphocitrate; D002118:Calcium
references.citation: Rheumatol Int. 1992;12(2):53-9
references.pmid: 1411083
references.citation: Curr Opin Rheumatol. 2005 May;17(3):336-40
references.pmid: 15838247
references.citation: Eur Cytokine Netw. 2005 Dec;16(4):289-92
references.pmid: 16464743
references.citation: Arthritis Rheum. 2004 May;50(5):1642-9
references.pmid: 15146435
references.citation: Calcif Tissue Int. 2008 Jan;82(1):77-86
references.pmid: 18175032
references.citation: Curr Opin Rheumatol. 2000 May;12(3):223-7
references.pmid: 10803753
references.citation: J Immunol. 1994 Jun 15;152(12):5940-8
references.pmid: 8207219
references.citation: Arthritis Rheum. 2006 Aug;54(8):2452-61
references.pmid: 16869019
references.citation: Osteoarthritis Cartilage. 2007 Jul;15(7):743-51
references.pmid: 17376709
references.citation: Oncogene. 2003 Oct 9;22(44):6839-44
references.pmid: 14534529
references.citation: Curr Rheumatol Rep. 2001 Feb;3(1):24-8
references.pmid: 11794133
references.citation: Histochem Cell Biol. 2001 Apr;115(4):317-23
references.pmid: 11405060
references.citation: J Rheumatol. 1997 Feb;24(2):365-71
references.pmid: 9034998
references.citation: Arthritis Rheum. 2009 Oct;60(10):2926-34
references.pmid: 19790065
references.citation: J Biol Chem. 2002 Jan 11;277(2):1544-52
references.pmid: 11682465
references.citation: Biol Trace Elem Res. 2001 Mar;79(3):247-56
references.pmid: 11354349
references.citation: Breast Cancer Res Treat. 2003 May;79(2):253-63
references.pmid: 12825860
references.citation: Rheumatol Int. 2010 Mar;30(5):623-31
references.pmid: 19639325
references.citation: Biomarkers. 2007 Jul-Aug;12(4):384-402
references.pmid: 17564844
references.citation: J Rheumatol Suppl. 1997 Jul;49:20-4
references.pmid: 9249647
references.citation: Z Orthop Ihre Grenzgeb. 2005 Jul-Aug;143(4):424-30
references.pmid: 16118758
references.citation: Arthritis Rheum. 2009 Sep;60(9):2694-703
references.pmid: 19714647
references.citation: Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20602-7
references.pmid: 23185004
references.citation: Radiology. 2009 Sep;252(3):772-80
references.pmid: 19635831
references.citation: J Biol Chem. 1997 Jul 25;272(30):18920-5
references.pmid: 9228071
references.citation: Biochim Biophys Acta. 1996 Mar 1;1315(2):105-11
references.pmid: 8608166
references.citation: Acta Orthop. 2007 Oct;78(5):687-92
references.pmid: 17966030
references.citation: J Org Chem. 2007 Feb 16;72(4):1468-71
references.pmid: 17288391
references.citation: Arthritis Rheum. 1995 Apr;38(4):477-84
references.pmid: 7536415
references.citation: J Cell Physiol. 2004 Nov;201(2):167-80
references.pmid: 15334652
references.citation: Brain Tumor Pathol. 2005;22(1):1-8
references.pmid: 18095097
references.citation: Mayo Clin Health Lett. 1999 Apr;17(4):7
references.pmid: 10100465
references.citation: Arthritis Rheum. 1976 May-Jun;19 Suppl 3:353-7
references.pmid: 938599
references.citation: J Investig Med. 1998 Apr;46(4):134-9
references.pmid: 9635372
references.citation: Atherosclerosis. 1987 May;65(1-2):117-24
references.pmid: 3038134
references.citation: J Rheumatol. 2002 Mar;29(3):570-4
references.pmid: 11908575
references.citation: Biochemistry. 1980 Apr 29;19(9):1983-8
references.pmid: 7378389
references.citation: Ann Rheum Dis. 1999 Aug;58(8):488-92
references.pmid: 10419867
references.citation: J Rheumatol. 2009 Jan;36(1):141-55
references.pmid: 19040300
references.citation: Osteoarthritis Cartilage. 2009 Apr;17(4):547-55
references.pmid: 18930415
references.citation: Front Biosci. 2005 Jan 01;10:803-8
references.pmid: 15569620
references.citation: Arthritis Res Ther. 2010;12(2):R56
references.pmid: 20353559
references.citation: Exp Clin Endocrinol Diabetes. 1998;106(6):506-13
references.pmid: 10079033
references.citation: Ann Rheum Dis. 2005 Sep;64(9):1263-7
references.pmid: 15731292
references.citation: Arthritis Rheum. 2002 Mar;46(3):694-703
references.pmid: 11920405
references.citation: Ann Rheum Dis. 2007 Dec;66(12):1599-603
references.pmid: 17491096
references.citation: Curr Rheumatol Rep. 2009 Apr;11(2):148-53
references.pmid: 19296888
references.citation: Ann Rheum Dis. 1997 Sep;56(9):550-7
references.pmid: 9370880
references.citation: Arthritis Rheum. 2000 Feb;43(2):275-80
references.pmid: 10693866
references.citation: Biochem Biophys Res Commun. 2003 Dec 26;312(4):1053-9
references.pmid: 14651978
references.citation: J Rheumatol. 1991 Jun;18(6):861-6
references.pmid: 1895267
references.citation: Osteoarthritis Cartilage. 2003 Jan;11(1):50-4
references.pmid: 12505487