title: Prolactin promotes cartilage survival and attenuates inflammation in inflammatory arthritis.
abstract: Chondrocytes are the only cells in cartilage, and their death by apoptosis contributes to cartilage loss in inflammatory joint diseases, such as rheumatoid arthritis (RA). A putative therapeutic intervention for RA is the inhibition of apoptosis-mediated cartilage degradation. The hormone prolactin (PRL) frequently increases in the circulation of patients with RA, but the role of hyperprolactinemia in disease activity is unclear. Here, we demonstrate that PRL inhibits the apoptosis of cultured chondrocytes in response to a mixture of proinflammatory cytokines (TNF-α, IL-1β, and IFN-γ) by preventing the induction of p53 and decreasing the BAX/BCL-2 ratio through a NO-independent, JAK2/STAT3-dependent pathway. Local treatment with PRL or increasing PRL circulating levels also prevented chondrocyte apoptosis evoked by injecting cytokines into the knee joints of rats, whereas the proapoptotic effect of cytokines was enhanced in PRL receptor-null (Prlr(-/-)) mice. Moreover, eliciting hyperprolactinemia in rats before or after inducing the adjuvant model of inflammatory arthritis reduced chondrocyte apoptosis, proinflammatory cytokine expression, pannus formation, bone erosion, joint swelling, and pain. These results reveal the protective effect of PRL against inflammation-induced chondrocyte apoptosis and the therapeutic potential of hyperprolactinemia to reduce permanent joint damage and inflammation in RA.
authors.affiliation: Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus UNAM-Juriquilla, Querétaro, México.
authors.forename: Norma
authors.initials: N
authors.lastname: Adán
authors.forename: Jessica
authors.initials: J
authors.lastname: Guzmán-Morales
authors.forename: Maria G
authors.initials: MG
authors.lastname: Ledesma-Colunga
authors.forename: Sonia I
authors.initials: SI
authors.lastname: Perales-Canales
authors.forename: Andrés
authors.initials: A
authors.lastname: Quintanar-Stéphano
authors.forename: Fernando
authors.initials: F
authors.lastname: López-Barrera
authors.forename: Isabel
authors.initials: I
authors.lastname: Méndez
authors.forename: Bibiana
authors.initials: B
authors.lastname: Moreno-Carranza
authors.forename: Jakob
authors.initials: J
authors.lastname: Triebel
authors.forename: Nadine
authors.initials: N
authors.lastname: Binart
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Martínez de la Escalera
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Thebault
authors.forename: Carmen
authors.initials: C
authors.lastname: Clapp
mesh_terms: D000818:Animals; D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000473:pathology / Q000503:physiopathology*; D002358:Cartilage, Articular / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000502:physiology; D016207:Cytokines / Q000502:physiology; D018492:Dopamine Antagonists / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology; D011388:Prolactin / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011981:Receptors, Prolactin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D016207:Cytokines; D018492:Dopamine Antagonists; D011981:Receptors, Prolactin; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D009569:Nitric Oxide; D011388:Prolactin; D053614:Janus Kinase 2; D006220:Haloperidol
references.citation: J Immunol. 1999 Jul 15;163(2):576-82
references.pmid: 10395643
references.citation: Clin Exp Rheumatol. 1996 Mar-Apr;14(2):155-62
references.pmid: 8737721
references.citation: J Musculoskelet Neuronal Interact. 2001 Jun;1(4):377-85
references.pmid: 15758488
references.citation: Ann Rheum Dis. 2001 Mar;60(3):242-7
references.pmid: 11171686
references.citation: Endocr Rev. 2008 Feb;29(1):1-41
references.pmid: 18057139
references.citation: Autoimmunity. 2007 Jun;40(4):333-6
references.pmid: 17516222
references.citation: Mol Cell Endocrinol. 1996 Mar 25;117(2):131-40
references.pmid: 8737372
references.citation: Lupus. 1998;7(8):569-70
references.pmid: 9863903
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 2006 May;373(2):140-7
references.pmid: 16703402
references.citation: Arthritis Rheum. 2000 May;43(5):1010-5
references.pmid: 10817553
references.citation: Br J Pharmacol. 2000 Dec;131(8):1513-20
references.pmid: 11139426
references.citation: Dev Biol. 2007 Dec 15;312(2):572-81
references.pmid: 17997399
references.citation: Science. 1999 Feb 26;283(5406):1277-8
references.pmid: 10084932
references.citation: Arthritis Rheum. 1998 Sep;41(9):1632-8
references.pmid: 9751096
references.citation: J Rheumatol. 1993 Jul;20(7):1143-51
references.pmid: 8371207
references.citation: Autoimmun Rev. 2007 Sep;6(8):537-42
references.pmid: 17854745
references.citation: Mult Scler. 2013 Jan;19(1):15-23
references.pmid: 22933621
references.citation: Nat Rev Immunol. 2007 Jun;7(6):429-42
references.pmid: 17525752
references.citation: J Endocrinol. 2000 Jul;166(1):53-62
references.pmid: 10856883
references.citation: Clin Orthop Relat Res. 2001 Oct;(391 Suppl):S108-15
references.pmid: 11603695
references.citation: Endocrinology. 1999 Jan;140(1):96-105
references.pmid: 9886812
references.citation: J Cell Physiol. 2010 Mar;222(3):502-8
references.pmid: 20020442
references.citation: Arthritis Rheum. 1991 May;34(5):606-15
references.pmid: 2025312
references.citation: EMBO J. 1991 Dec;10(13):4025-31
references.pmid: 1721867
references.citation: Eur Cytokine Netw. 2007 Sep;18(3):127-35
references.pmid: 17823080
references.citation: Br J Clin Pharmacol. 1981 Oct;12(4):579-81
references.pmid: 7295491
references.citation: Brain Behav Immun. 1992 Dec;6(4):409-17
references.pmid: 1490033
references.citation: J Mol Endocrinol. 1997 Dec;19(3):347-50
references.pmid: 9460655
references.citation: Arch Neurol. 2009 Aug;66(8):958-63
references.pmid: 19506118
references.citation: Proc Natl Acad Sci U S A. 2007 May 1;104(18):7391-6
references.pmid: 17463090
references.citation: Biomed Pharmacother. 1999 Jun;53(5-6):218-22
references.pmid: 10424242
references.citation: Am J Physiol Cell Physiol. 2001 Sep;281(3):C833-9
references.pmid: 11502560
references.citation: Endocr Rev. 1986 Aug;7(3):302-13
references.pmid: 3017688
references.citation: Clin Exp Med. 2006 Mar;6(1):13-9
references.pmid: 16550339
references.citation: Swiss Med Wkly. 2012 Aug 06;142:w13650
references.pmid: 22869348
references.citation: J Rheumatol. 1999 Sep;26(9):1890-900
references.pmid: 10493666
references.citation: Ann Rheum Dis. 2000 Dec;59(12):959-65
references.pmid: 11087699
references.citation: Mol Endocrinol. 2004 May;18(5):1171-84
references.pmid: 14963111
references.citation: Vet J. 2003 Sep;166(2):140-58
references.pmid: 12902179
references.citation: Curr Opin Rheumatol. 1998 May;10(3):263-8
references.pmid: 9608331
references.citation: Ann Rheum Dis. 1990 Sep;49(9):676-81
references.pmid: 1700673
references.citation: Endocr Rev. 2000 Jun;21(3):292-312
references.pmid: 10857555
references.citation: Endocrinology. 2001 Sep;142(9):4086-94
references.pmid: 11517188
references.citation: Immunology. 1992 Nov;77(3):449-55
references.pmid: 1478689
references.citation: Ann N Y Acad Sci. 2002 Jun;966:252-7
references.pmid: 12114280
references.citation: Autoimmun Rev. 2012 May;11(6-7):A465-70
references.pmid: 22155203
references.citation: J Orthop Res. 2004 Jan;22(1):140-4
references.pmid: 14656672
references.citation: Arthritis Rheum. 1999 Jul;42(7):1528-37
references.pmid: 10403282
references.citation: Clin Exp Rheumatol. 2005 May-Jun;23(3):292-6
references.pmid: 15971415
references.citation: Am J Psychiatry. 2000 Apr;157(4):514-20
references.pmid: 10739409
references.citation: Arthritis Res Ther. 2008;10(1):R9
references.pmid: 18205922
references.citation: Schizophr Res. 2000 Apr 7;42(2):157-64
references.pmid: 10742653
references.citation: Mol Endocrinol. 1997 Aug;11(9):1213-22
references.pmid: 9259313
references.citation: Adv Drug Deliv Rev. 2006 May 20;58(2):128-49
references.pmid: 16616393
references.citation: Semin Arthritis Rheum. 2001 Aug;31(1):21-32
references.pmid: 11503136
references.citation: Anat Rec. 1998 Apr;250(4):418-25
references.pmid: 9566531
references.citation: Recent Prog Horm Res. 2002;57:435-55
references.pmid: 12017556
references.citation: Acta Biomed. 2007;78 Suppl 1:255-61
references.pmid: 17465339
references.citation: Arthritis Rheum. 1996 Mar;39(3):478-88
references.pmid: 8607897
references.citation: J Cell Biochem. 2007 Aug 15;101(6):1520-31
references.pmid: 17492650
references.citation: EMBO J. 1997 Dec 1;16(23):6926-35
references.pmid: 9384572
references.citation: Brain. 2004 Jun;127(Pt 6):1353-60
references.pmid: 15130950
references.citation: J Clin Immunol. 1992 May;12(3):210-5
references.pmid: 1400902
references.citation: J Cell Sci. 2006 May 1;119(Pt 9):1790-800
references.pmid: 16608881
references.citation: Mol Cell Endocrinol. 2002 Apr 25;190(1-2):51-63
references.pmid: 11997178
references.citation: Folia Histochem Cytobiol. 2012 Apr 24;50(1):137-43
references.pmid: 22532149
references.citation: Life Sci. 1990;46(20):1407-20
references.pmid: 2189051
references.citation: Clin Rev Allergy Immunol. 2011 Feb;40(1):50-9
references.pmid: 19911311
references.citation: J Clin Endocrinol Metab. 1980 Nov;51(5):1058-63
references.pmid: 7419681
references.citation: Ann Rheum Dis. 1999 Sep;58(9):585-7
references.pmid: 10460194
references.citation: Arthritis Rheum. 2003 Oct;48(10):2845-54
references.pmid: 14558090
references.citation: Am J Manag Care. 2010 Nov;16(9 Suppl):S249-58
references.pmid: 21517638
references.citation: Immunol Res. 2012 Jun;52(3):169-75
references.pmid: 21979468
references.citation: J Orthop Sci. 2000;5(2):150-6
references.pmid: 10982649
references.citation: FEBS Lett. 2003 Jun 5;544(1-3):171-5
references.pmid: 12782310
references.citation: Arch Oral Biol. 2003 Dec;48(12):825-34
references.pmid: 14596872
references.citation: J Clin Invest. 2002 Oct;110(7):973-81
references.pmid: 12370275
references.citation: J Endocrinol. 2006 May;189(2):R1-8
references.pmid: 16648286
references.citation: Clin Exp Immunol. 1986 May;64(2):399-406
references.pmid: 3091304
references.citation: Osteoarthritis Cartilage. 2003 Sep;11(9):681-7
references.pmid: 12954239