Cervical softening during pregnancy: regulated changes in collagen cross-linking and composition of matricellular proteins in the mouse.
A greater understanding of the parturition process is essential in the prevention of preterm birth, which occurs in 12.7% of infants born in the United States annually. Cervical remodeling is a critical component of this process. Beginning early in pregnancy, remodeling requires cumulative, progressive changes in the cervical extracellular matrix (ECM) that result in reorganization of collagen fibril structure with a gradual loss of tensile strength. In the current study, we undertook a detailed biochemical analysis of factors in the cervix that modulate collagen structure during early mouse pregnancy, including expression of proteins involved in processing of procollagen, assembly of collagen fibrils, cross-link formation, and deposition of collagen in the ECM. Changes in these factors correlated with changes in the types of collagen cross-links formed and packing of collagen fibrils as measured by electron microscopy. Early in pregnancy there is a decline in expression of two matricellular proteins, thrombospondin 2 and tenascin C, as well as a decline in expression of lysyl hydroxylase, which is involved in cross-link formation. These changes are accompanied by a decline in both HP and LP cross-links by gestation Days 12 and 14, respectively, as well as a progressive increase in collagen fibril diameter. In contrast, collagen abundance remains constant over the course of pregnancy. We conclude that early changes in tensile strength during cervical softening result in part from changes in the number and type of collagen cross-links and are associated with a decline in expression of two matricellular proteins thrombospondin 2 and tenascin C.
Department of Obstetrics and Gynecology, The Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Meredith L
ML
Akins
Katherine
K
Luby-Phelps
Ruud A
RA
Bank
Mala
M
Mahendroo
D000818:Animals; D020070:Cervical Ripening / Q000378:metabolism*; D003094:Collagen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D024022:Fibrillar Collagens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D011347:Procollagen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D019063:Tenascin / Q000235:genetics / Q000378:metabolism; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism; D000099262:Thrombospondin 2
D003094:Collagen; D016326:Extracellular Matrix Proteins; D024022:Fibrillar Collagens; D007527:Isoenzymes; D011257:Pregnancy Proteins; D011347:Procollagen; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D012333:RNA, Messenger; D019063:Tenascin; D019699:Thrombospondins; D000099262:Thrombospondin 2
J Mol Biol. 1998 Apr 24;278(1):195-204
9571043
Biol Reprod. 2004 Feb;70(2):385-90
14561659
Endocrinology. 1981 Aug;109(2):618-21
6113953
Ann N Y Acad Sci. 1990;580:214-24
2337298
J Cell Biol. 2000 Sep 18;150(6):1499-506
10995453
Rheumatology (Oxford). 2010 Feb;49(2):231-9
19955224
Am J Obstet Gynecol. 2000 Apr;182(4):805-11; discussion 811-2
10764456
Mol Endocrinol. 1997 Jun;11(7):917-27
9178751
J Histochem Cytochem. 1999 Dec;47(12):1495-506
10567433
J Cell Biol. 1997 Feb 10;136(3):729-43
9024701
Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1852-6
9050868
Curr Biol. 2000 Dec 14-28;10(24):R912-5
11137028
FASEB J. 2002 May;16(7):673-80
11978731
J Biol Chem. 2007 Mar 2;282(9):6588-96
17197443
Semin Cell Dev Biol. 1999 Oct;10(5):455-64
10597628
J Biomech Eng. 2010 Feb;132(2):021003
20370240
J Biol Chem. 2003 Oct 17;278(42):40967-72
12881513
J Cell Biol. 1998 Jan 26;140(2):419-30
9442117
Mol Biol Cell. 2000 Oct;11(10):3353-64
11029041
Biochem J. 1991 Apr 15;275 ( Pt 2):515-20
2025230
Curr Opin Cell Biol. 2002 Oct;14(5):608-16
12231357
Annu Rev Biochem. 1995;64:403-34
7574488
Am J Pathol. 2007 Feb;170(2):578-89
17255326
Reprod Sci. 2007 Dec;14(8 Suppl):53-62
18089611
Biochem J. 1996 May 15;316 ( Pt 1):1-11
8645190
J Invest Dermatol. 2003 Jun;120(6):949-55
12787119
Placenta. 2009 Mar;30(3):207-15
19152976
Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4449-54
10200282
JAMA. 2001 Sep 19;286(11):1340-8
11560539
J Biol Chem. 1979 Jan 10;254(1):224-32
569151
FEBS J. 2007 Aug;274(16):4246-55
17651433
Matrix Biol. 2010 May;29(4):248-53
20080181
J Cell Sci. 2005 Apr 1;118(Pt 7):1341-53
15788652
Biochim Biophys Acta. 1998 Mar 5;1406(2):203-13
9573366
Am J Obstet Gynecol. 2001 Mar;184(4):652-5
11262467
Clin Obstet Gynecol. 1995 Jun;38(2):267-79
7554594
Obstet Gynecol. 1993 Jan;81(1):88-92
8416467
J Chromatogr B Biomed Sci Appl. 1997 Dec 5;703(1-2):37-44
9448060
Clin Chim Acta. 1967 Nov;18(2):267-73
4864804
Am J Obstet Gynecol. 1974 Nov 1;120(5):641-51
4278606
Biol Reprod. 1990 Jan;42(1):87-97
2310820
Am J Med Genet A. 2004 Dec 1;131(2):115-20
15523624
J Biomed Opt. 2010 Mar-Apr;15(2):026020
20459265
Annu Rev Biochem. 1984;53:717-48
6148038
Biol Reprod. 2003 Nov;69(5):1608-14
12855606
Semin Reprod Med. 2007 Jan;25(1):69-79
17205425
Biol Reprod. 2005 Nov;73(5):1046-56
16034000
J Biol Chem. 2007 Jul 27;282(30):22062-71
17522057
Reproduction. 2007 Aug;134(2):327-40
17660242
Arch Gynakol. 1976 Apr 29;220(4):275-80
946942
J Biol Chem. 2009 Nov 6;284(45):30917-24
19762917
J Histochem Cytochem. 2004 Dec;52(12):1665-74
15557221
Matrix Biol. 2000 Dec;19(7):581-96
11102748
Connect Tissue Res. 1991;26(3):199-205
1769238