title: Neutralizing TIMP1 restores fecundity in a rat model of endometriosis and treating control rats with TIMP1 causes anomalies in ovarian function and embryo development.
abstract: Human and rat endometriotic lesions synthesize and secrete tissue inhibitor of metalloproteinase 1 (TIMP1). More TIMP1 localizes in the ovarian theca in an established rat model for endometriosis (Endo) when compared to surgical controls (Sham). We hypothesized that endometriotic TIMP1 secreted into peritoneal fluid (PF) negatively affects ovarian function and embryogenesis by altering the balance of matrix metalloproteinases (MMPs) and TIMPs. Three experiments were performed modulating TIMP1 in vitro and in vivo to investigate ovarian and embryonic anomalies. The first experiment demonstrated control embryos treated in vitro with endometriotic PF concentrations of TIMP1 developed abnormally. In the second experiment where TIMP1 was modulated in vivo, TIMP1-treated Sham rats had fewer zygotes, ovarian follicles, and corpora lutea (CLs) and poorer embryo quality and development, which is analogous to the findings in Endo rats. Importantly, Endo rats treated with a TIMP1 function-blocking antibody had zygote, follicle, and CL numbers and embryo quality similar to Sham rats. In addition, more TIMP1 inhibitory activity was found in ovaries from Endo and TIMP1-treated Sham rats than in ovaries from Sham or TIMP1 antibody-treated Endo rats. In experiment three, control rats (no surgery) treated with Endo PF had fewer follicles and CLs and increased TIMP1 localization in the ovarian theca whereas treatment with Endo PF stripped of TIMP1 or with Sham PF had no effect, providing further evidence that endometriotic TIMP1 sequesters in the ovary and inhibits MMPs necessary for ovulation. Collectively, these results showed that excessive TIMP1 was deleterious to ovulation and embryo development. Thus, novel TIMP1-modulating therapies may be developed to alleviate infertility in women with endometriosis.
authors.affiliation: Department of Obstetrics, Division of Animal Sciences, College of Agriculture, Food and Natural Resources, University of Missouri-Columbia, Columbia, Missouri 65212, USA.
authors.forename: Julie A W
authors.initials: JA
authors.lastname: Stilley
authors.forename: Julie A
authors.initials: JA
authors.lastname: Birt
authors.forename: Susan C
authors.initials: SC
authors.lastname: Nagel
authors.forename: Miriam
authors.initials: M
authors.lastname: Sutovsky
authors.forename: Peter
authors.initials: P
authors.lastname: Sutovsky
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Sharpe-Timms
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001202:Ascitic Fluid / Q000737:chemistry; D003338:Corpus Luteum / Q000187:drug effects; D004195:Disease Models, Animal; D046149:Embryo Culture Techniques; D047108:Embryonic Development / Q000187:drug effects*; D004715:Endometriosis / Q000150:complications / Q000378:metabolism*; D005260:Female; D007247:Infertility, Female / Q000209:etiology / Q000628:therapy*; D061965:Matrix Metalloproteinase Inhibitors; D006080:Ovarian Follicle / Q000187:drug effects; D010053:Ovary / Q000737:chemistry / Q000187:drug effects* / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D015053:Zygote / Q000187:drug effects
chemical_list: D000906:Antibodies; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1
references.citation: Biol Reprod. 1993 Jun;48(6):1334-40
references.pmid: 8318587
references.citation: Am J Obstet Gynecol. 1991 Jan;164(1 Pt 1):187-94
references.pmid: 1986606
references.citation: Fertil Steril. 2010 Oct;94(5):1894-9
references.pmid: 19896655
references.citation: Biol Reprod. 1992 Feb;46(2):256-64
references.pmid: 1311210
references.citation: Fertil Steril. 2003 Sep;80 Suppl 2:736-42
references.pmid: 14505747
references.citation: Fertil Steril. 1993 Nov;60(5):839-51
references.pmid: 7693516
references.citation: Endocrinology. 1990 Jul;127(1):25-31
references.pmid: 2113868
references.citation: Fertil Steril. 2001 Jan;75(1):152-9
references.pmid: 11163831
references.citation: Biochem Biophys Res Commun. 1999 Apr 13;257(2):494-9
references.pmid: 10198240
references.citation: Radiat Res. 2007 Jun;167(6):663-74
references.pmid: 17523843
references.citation: Ann N Y Acad Sci. 2002 Mar;955:318-27; discussion 340-2, 396-406
references.pmid: 11949958
references.citation: Acta Obstet Gynecol Scand. 1995 Aug;74(7):539-43
references.pmid: 7618453
references.citation: Fertil Steril. 1988 Nov;50(5):711-5
references.pmid: 3181482
references.citation: Neurosci Lett. 2001 Jun 29;306(3):185-8
references.pmid: 11406326
references.citation: Genes Dev. 1989 Jun;3(6):848-59
references.pmid: 2744464
references.citation: Biol Reprod. 2000 Sep;63(3):905-12
references.pmid: 10952938
references.citation: J Clin Endocrinol Metab. 1995 Dec;80(12):3784-7
references.pmid: 8530636
references.citation: Biol Reprod. 2001 May;64(5):1285-96
references.pmid: 11319131
references.citation: Hum Reprod. 1998 Jul;13(7):1825-30
references.pmid: 9740433
references.citation: J Clin Endocrinol Metab. 2001 Jun;86(6):2553-61
references.pmid: 11397854
references.citation: Fertil Steril. 1985 Nov;44(5):684-94
references.pmid: 4054348
references.citation: Fertil Steril. 1988 Jan;49(1):47-51
references.pmid: 3275551
references.citation: Microvasc Res. 2003 Jan;65(1):9-17
references.pmid: 12535866
references.citation: Fertil Steril. 1998 May;69(5):916-23
references.pmid: 9591503
references.citation: Mol Reprod Dev. 2001 Jun;59(2):159-67
references.pmid: 11389550
references.citation: Mol Hum Reprod. 1997 Jan;3(1):27-45
references.pmid: 9239706
references.citation: Hum Reprod. 1997 Jan;12(1):101-6
references.pmid: 9043912
references.citation: J Endocrinol. 1998 Aug;158(2):221-8
references.pmid: 9771466
references.citation: J Assist Reprod Genet. 1998 Oct;15(9):530-4
references.pmid: 9822979
references.citation: Fertil Steril. 1984 Jun;41(6):933-5
references.pmid: 6427022
references.citation: Biol Reprod. 2001 Oct;65(4):1297-303
references.pmid: 11566756
references.citation: Hum Reprod Update. 2002 Jan-Feb;8(1):95-103
references.pmid: 11866246
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Cancer Res. 2006 Jul 1;66(13):6699-707
references.pmid: 16818644
references.citation: Hum Reprod Update. 2000 Jan-Feb;6(1):56-66
references.pmid: 10711830
references.citation: Biol Reprod. 1997 May;56(5):1181-8
references.pmid: 9160717
references.citation: Biol Reprod. 2004 Nov;71(5):1598-604
references.pmid: 15240428
references.citation: Am J Obstet Gynecol. 1993 Sep;169(3):676-82
references.pmid: 8372879
references.citation: Front Biosci. 2005 Jan 01;10:569-75
references.pmid: 15574393
references.citation: Semin Reprod Med. 2003 May;21(2):155-64
references.pmid: 12917785
references.citation: Trends Genet. 1990 Apr;6(4):121-5
references.pmid: 2132731
references.citation: Semin Reprod Med. 2003 May;21(2):183-92
references.pmid: 12917788
references.citation: Fertil Steril. 1988 Nov;50(5):716-20
references.pmid: 3181483
references.citation: Biol Reprod. 1999 Apr;60(4):954-8
references.pmid: 10084971
references.citation: Biol Reprod. 2009 Apr;80(4):649-56
references.pmid: 19020297