Skip to main content

Advertisement

SpringerLink
Log in

Uterine Collagen Cross-Linking: Biology, Role in Disorders, and Therapeutic Implications

  • Review
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Collagen is an essential constituent of the uterine extracellular matrix that provides biomechanical strength, resilience, structural integrity, and the tensile properties necessary for the normal functioning of the uterus. Cross-linking is a fundamental step in collagen biosynthesis and is critical for its normal biophysical properties. This step occurs enzymatically via lysyl oxidase (LOX) or non-enzymatically with the production of advanced glycation end-products (AGEs). Cross-links found in uterine tissue include the reducible dehydro-dihydroxylysinonorleucine (deH-DHLNL), dehydro-hydroxylysinonorleucine (deH-HLNL), and histidinohydroxymerodesmosine (HHMD); and the non-reducible pyridinoline (PYD), deoxy-pyridinoline (DPD); and a trace of pentosidine (PEN). Collagen cross-links are instrumental for uterine tissue integrity and the continuation of a healthy pregnancy. Decreased cervical cross-link density is observed in preterm birth, whereas increased tissue stiffness caused by increased cross-link density is a pathogenic feature of uterine fibroids. AGEs disrupt embryo development, decidualization, implantation, and trophoblast invasion. Uterine collagen cross-linking regulators include steroid hormones, such as progesterone and estrogen, prostaglandins, proteoglycans, metalloproteinases, lysyl oxidases, nitric oxide, nicotine, and vitamin D. Thus, uterine collagen cross-linking presents an opportunity to design therapeutic targets and warrants further investigation in common uterine disorders, such as uterine fibroids, cervical insufficiency, preterm birth, dystocia, endometriosis, and adenomyosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Fratzl P. Collagen: structure and mechanics, an introduction. Collagen, Boston, MA: Springer US; 2008. p. 1–13. https://doi.org/10.1007/978-0-387-73906-9_1.

    Book  Google Scholar 

  2. Oxlund BS, Ørtoft G, Brüel A, Danielsen CC, Bor P, Oxlund H, et al. Collagen concentration and biomechanical properties of samples from the lower uterine cervix in relation to age and parity in non-pregnant women. Reprod Biol Endocrinol. 2010;8:82. https://doi.org/10.1186/1477-7827-8-82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sorushanova A, Delgado LM, Wu Z, Shologu N, Kshirsagar A, Raghunath R, et al. The collagen suprafamily: from biosynthesis to advanced biomaterial development. Adv Mater. 2019;31:1801651. https://doi.org/10.1002/adma.201801651.

  4. Yoshida K, Reeves C, Vink J, Kitajewski J, Wapner R, Jiang H, et al. Cervical collagen network remodeling in normal pregnancy and disrupted parturition in Antxr2 deficient mice. J Biomech Eng. 2014;136:021017. https://doi.org/10.1115/1.4026423.

  5. Pickering JG. Regulation of vascular cell behavior by collagen. Circ Res. 2001;88:458–9. https://doi.org/10.1161/01.RES.88.5.458.

    Article  CAS  PubMed  Google Scholar 

  6. Jones JL, Walker RA. Integrins: a role as cell signalling molecules. Mol Pathol. 1999;52:208–13. https://doi.org/10.1136/mp.52.4.208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Aplin JD. The Endometrium. 2nd ed. CRC Press; 2008. https://doi.org/10.3109/9780203091500.

    Book  Google Scholar 

  8. Heino J. The collagen family members as cell adhesion proteins. BioEssays. 2007;29:1001–10. https://doi.org/10.1002/bies.20636.

    Article  CAS  PubMed  Google Scholar 

  9. Snedeker JG, Gautieri A. The role of collagen crosslinks in ageing and diabetes - the good, the bad, and the ugly. Muscles Ligaments Tendons J. 2014;4:303–8.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Avery NC, Bailey AJ. Restraining cross-links responsible for the mechanical properties of collagen fibers: natural and artificial. Collagen, Boston, MA: Springer US; 2008. p. 81–110. https://doi.org/10.1007/978-0-387-73906-9_4.

    Book  Google Scholar 

  11. Kong W, Lyu C, Liao H, Du Y. Collagen crosslinking: effect on structure, mechanics and fibrosis progression. Biomed Mater. 2021;16:062005. https://doi.org/10.1088/1748-605X/ac2b79.

  12. Canty EG, Kadler KE. Procollagen trafficking, processing and fibrillogenesis. J Cell Sci. 2005;118:1341–53. https://doi.org/10.1242/jcs.01731.

    Article  CAS  PubMed  Google Scholar 

  13. Skopinska-Wisniewska J, Kuderko J, Bajek A, Maj M, Sionkowska A, Ziegler-Borowska M. Collagen/elastin hydrogels cross-linked by squaric acid. Mater Sci Eng C. 2016;60:100–8. https://doi.org/10.1016/j.msec.2015.11.015.

    Article  CAS  Google Scholar 

  14. Harvey RA, PhD. Lippincott’s illustrated reviews: biochemistry. 5th ed. Philadelphia: Wolters Kluwer Health; 2011.

    Google Scholar 

  15. Gordon MK, Hahn RA. Collagens. Cell Tissue Res. 2010;339:247–57. https://doi.org/10.1007/s00441-009-0844-4.

    Article  CAS  PubMed  Google Scholar 

  16. Myers KM, Socrate S, Paskaleva A, House M. A study of the anisotropy and tension/compression behavior of human cervical tissue. J Biomech Eng. 2010;132:021003. https://doi.org/10.1115/1.3197847.

  17. Mandell MS, Sodek J. Metabolism of collagen types I, III, and V in the estradiol-stimulated uterus. J Biol Chem. 1982;257:5268–73.

    Article  CAS  PubMed  Google Scholar 

  18. Aplin JD, Jones CJP. Extracellular matrix in endometrium and decidua. Placenta as a Model and a Source. Boston, MA: Springer US; 1989. p. 115–28. https://doi.org/10.1007/978-1-4613-0823-2_12.

    Book  Google Scholar 

  19. Zorn TM, Bevilacqua EM, Abrahamsohn PA. Collagen remodeling during decidualization in the mouse. Cell Tissue Res. 1986;244:443–8. https://doi.org/10.1007/BF00219220.

    Article  CAS  PubMed  Google Scholar 

  20. Wewer UM, Faber M, Liotta LA, Albrechtsen R. Immunochemical and ultrastructural assessment of the nature of the pericellular basement membrane of human decidual cells. Lab Invest. 1985;53:624–33.

    CAS  PubMed  Google Scholar 

  21. Pulkkinen MO, Lehto M, Jalkanen M, Näntö-Salonen K. Collagen types and fibronectin in the uterine muscle of normal and hypertensive pregnant patients. Am J Obstet Gynecol. 1984;149:711–7. https://doi.org/10.1016/0002-9378(84)90108-x.

    Article  CAS  PubMed  Google Scholar 

  22. Abedin MZ, Ayad S, Weiss JB. Type V collagen: the presence of appreciable amounts of alpha 3(V) chain in uterus. Biochem Biophys Res Commun. 1981;102:1237–45. https://doi.org/10.1016/s0006-291x(81)80144-1.

    Article  CAS  PubMed  Google Scholar 

  23. Rehman KS, Yin S, Mayhew BA, Word RA, Rainey WE. Human myometrial adaptation to pregnancy: cDNA microarray gene expression profiling of myometrium from non-pregnant and pregnant women. Mol Hum Reprod. 2003;9:681–700. https://doi.org/10.1093/molehr/gag078.

    Article  CAS  PubMed  Google Scholar 

  24. Shynlova O, Mitchell JA, Tsampalieros A, Langille BL, Lye SJ. Progesterone and gravidity differentially regulate expression of extracellular matrix components in the pregnant rat myometrium. Biol Reprod. 2004;70:986–92. https://doi.org/10.1095/biolreprod.103.023648.

    Article  CAS  PubMed  Google Scholar 

  25. Karkavelas G, Kefalides NA, Amenta PS, Martinez-Hernandez A. Comparative ultrastructural localization of collagen types III, IV, VI and laminin in rat uterus and kidney. J Ultrastruct Mol Struct Res. 1988;100:137–55. https://doi.org/10.1016/0889-1605(88)90021-3.

    Article  CAS  PubMed  Google Scholar 

  26. Kao KYT, Leslie JG. Polymorphism in human uterine collagen. Connect Tissue Res. 1977;5:127–9. https://doi.org/10.3109/03008207709152239.

    Article  CAS  PubMed  Google Scholar 

  27. Kleissl HP, van der Rest M, Naftolin F, Glorieux FH, de Leon A. Collagen changes in the human uterine cervix at parturition. Am J Obstet Gynecol. 1978;130:748–53. https://doi.org/10.1016/0002-9378(78)90003-0.

    Article  CAS  PubMed  Google Scholar 

  28. Reiser K, McCormick RJ, Rucker RB. Enzymatic and nonenzymatic cross-linking of collagen and elastin. FASEB J. 1992;6:2439–49. https://doi.org/10.1096/fasebj.6.7.1348714.

    Article  CAS  PubMed  Google Scholar 

  29. Yeowell HN, Walker LC. Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers-Danlos syndrome type VI. Mol Genet Metab. 2000;71:212–24. https://doi.org/10.1006/mgme.2000.3076.

    Article  CAS  PubMed  Google Scholar 

  30. Pornprasertsuk S, Duarte WR, Mochida Y, Yamauchi M. Overexpression of lysyl hydroxylase-2b leads to defective collagen fibrillogenesis and matrix mineralization. J Bone Miner Res. 2005;20:81–7. https://doi.org/10.1359/JBMR.041026.

    Article  CAS  PubMed  Google Scholar 

  31. Yamauchi M, Shiiba M. Lysine hydroxylation and cross-linking of collagen. Methods Mol Biol. 2008;446:95–108. https://doi.org/10.1007/978-1-60327-084-7_7.

    Article  CAS  PubMed  Google Scholar 

  32. Mercer DK, Nicol PF, Kimbembe C, Robins SP. Identification, expression, and tissue distribution of the three rat lysyl hydroxylase isoforms. Biochem Biophys Res Commun. 2003;307:803–9. https://doi.org/10.1016/s0006-291x(03)01262-2.

    Article  CAS  PubMed  Google Scholar 

  33. Lucero HA, Kagan HM. Lysyl oxidase: an oxidative enzyme and effector of cell function. Cell Mol Life Sci. 2006;63:2304–16. https://doi.org/10.1007/s00018-006-6149-9.

    Article  CAS  PubMed  Google Scholar 

  34. Eyre DR, Paz MA, Gallop PM. Cross-linking in collagen and elastin. Annu Rev Biochem. 1984;53:717–48. https://doi.org/10.1146/annurev.bi.53.070184.003441.

    Article  CAS  PubMed  Google Scholar 

  35. Henkel W, Rauterberg J, Glanville RW. Isolation of crosslinked peptides from insoluble human leiomyoma. Eur J Biochem. 1979;96:249–56. https://doi.org/10.1111/j.1432-1033.1979.tb13035.x.

    Article  CAS  PubMed  Google Scholar 

  36. Hulmes DJS. Collagen diversity, synthesis and assembly. Collagen, Boston, MA: Springer US; 2008. p. 15–47. https://doi.org/10.1007/978-0-387-73906-9_2.

    Book  Google Scholar 

  37. Robins SP. Biochemistry and functional significance of collagen cross-linking. Biochem Soc Trans. 2007;35:849–52. https://doi.org/10.1042/BST0350849.

    Article  CAS  PubMed  Google Scholar 

  38. Eyre DR, Wu JJ. Collagen cross-links. In: Brinckmann J, Notbohm H, Müller PK (eds.) Collagen. Topics in Current Chemistry, vol. 247. Berlin, Heidelberg: Springer. https://doi.org/10.1007/b103828.

  39. Gaar J, Naffa R, Brimble M. Enzymatic and non-enzymatic crosslinks found in collagen and elastin and their chemical synthesis. Org Chem Front. 2020;7:2789–814. https://doi.org/10.1039/D0QO00624F.

    Article  CAS  Google Scholar 

  40. Saito M, Marumo K. Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporosis Int. 2010;21:195–214. https://doi.org/10.1007/s00198-009-1066-z.

    Article  CAS  Google Scholar 

  41. Gautieri A, Passini FS, Silván U, Guizar-Sicairos M, Carimati G, Volpi P, et al. Advanced glycation end-products: mechanics of aged collagen from molecule to tissue. Matrix Biol. 2017;59:95–108. https://doi.org/10.1016/j.matbio.2016.09.001.

    Article  CAS  PubMed  Google Scholar 

  42. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114:597–605. https://doi.org/10.1161/CIRCULATIONAHA.106.621854.

    Article  CAS  PubMed  Google Scholar 

  43. Reddy GK. AGE-related cross-linking of collagen is associated with aortic wall matrix stiffness in the pathogenesis of drug-induced diabetes in rats. Microvasc Res. 2004;68:132–42. https://doi.org/10.1016/j.mvr.2004.04.002.

    Article  CAS  PubMed  Google Scholar 

  44. McNerny EMB. Collagen cross-linking as a determinant of bone quality: the importance of cross-linking to mechanical properties as explored by cross-link inhibition and exercise. 2014. In: Dissertations and Theses (Ph.D. and Master’s). https://deepblue.lib.umich.edu/handle/2027.42/108862. Accessed 15 September 2022.

  45. DeGroot J, Verzijl N, Budde M, Bijlsma JWJ, Lafeber FPJG, TeKoppele JM. Accumulation of advanced glycation end products decreases collagen turnover by bovine chondrocytes. Exp Cell Res. 2001;266:303–10. https://doi.org/10.1006/excr.2001.5224.

    Article  CAS  PubMed  Google Scholar 

  46. Leppert PC, Jayes FL, Segars JH. The extracellular matrix contributes to mechanotransduction in uterine fibroids. Obstet Gynecol Int. 2014;2014:1–12. https://doi.org/10.1155/2014/783289.

    Article  Google Scholar 

  47. Schlembach D, MacKay L, Shi L, Maner WL, Garfield RE, Maul H. Cervical ripening and insufficiency: from biochemical and molecular studies to in vivo clinical examination. Eur J Obstet Gynecol Reprod Biol. 2009;144:S70–6. https://doi.org/10.1016/j.ejogrb.2009.02.036.

    Article  CAS  PubMed  Google Scholar 

  48. Woessner J, Brewer T. Formation and breakdown of collagen and elastin in the human uterus during pregnancy and post-partum involution. Biochem J. 1963;89:75–82. https://doi.org/10.1042/bj0890075.

    Article  CAS  PubMed  Google Scholar 

  49. Woessner J. Catabolism of collagen and non-collagen protein in the rat uterus during post-partum involution. Biochem J. 1962;83:304–14. https://doi.org/10.1042/bj0830304.

    Article  CAS  PubMed  Google Scholar 

  50. Ozasa H, Tominaga T, Nishimura T, Takeda T. Lysyl oxidase activity in the mouse uterine cervix is physiologically regulated by estrogen. Endocrinology. 1981;109:618–21. https://doi.org/10.1210/endo-109-2-618.

    Article  CAS  PubMed  Google Scholar 

  51. Gill EM, Malpica A, Alford RE, Nath AR, Follen M, Richards-Kortum RR, Ramanujam N. Relationship between collagen autofluorescence of the human cervix and menopausal status. Photochem Photobiol. 2003;77(6):653–8. https://doi.org/10.1562/0031-8655(2003)077<0653:rbcaot>2.0.co;2.

    Article  CAS  PubMed  Google Scholar 

  52. Kao K-YT, Hilker DM, McGavack TH. Connective tissue IV. Synthesis and turnover of proteins in tissues of rats. Exp Biol Med. 1961;106:121–4. https://doi.org/10.3181/00379727-106-26257.

    Article  CAS  Google Scholar 

  53. Kao K-YT, Hitt WE. The intermolecular cross-links in rat uterine collagen. Biochimica et Biophysica Acta (BBA) - Protein Structure. 1974;371:501–10. https://doi.org/10.1016/0005-2795(74)90046-4.

    Article  CAS  Google Scholar 

  54. Kao KY, Hitt WE, Leslie JG. The intermolecular cross-links in uterine collagens of guinea pig, pig, cow, and human beings. Proc Soc Exp Biol Med. 1976;151(2):385–9. https://doi.org/10.3181/00379727-151-39217.

    Article  CAS  PubMed  Google Scholar 

  55. Gunja-Smith Z, Woessner JF. Content of the collagen and elastin cross-links pyridinoline and the desmosines in the human uterus in various reproductive states. Am J Obstet Gynecol. 1985;153:92–5. https://doi.org/10.1016/0002-9378(85)90602-7.

    Article  CAS  PubMed  Google Scholar 

  56. Talbi S, Hamilton AE, Vo KC, Tulac S, Overgaard MT, Dosiou C, et al. Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women. Endocrinology. 2006;147:1097–121. https://doi.org/10.1210/en.2005-1076.

    Article  CAS  PubMed  Google Scholar 

  57. Granstrom L, Ekman G, Ulmsten U, Malmstrom A. Changes in the connective tissue of corpus and cervix uteri during ripening and labour in term pregnancy. BJOG. 1989;96:1198–202. https://doi.org/10.1111/j.1471-0528.1989.tb03196.x.

    Article  CAS  Google Scholar 

  58. Yoshida K, Jiang H, Kim MJ, Vink J, Cremers S, Paik D, et al. Quantitative evaluation of collagen crosslinks and corresponding tensile mechanical properties in mouse cervical tissue during normal pregnancy. PLoS One. 2014;9:e112391. https://doi.org/10.1371/journal.pone.0112391.

  59. Zork NM, Myers KM, Yoshida K, Cremers S, Jiang H, Ananth C v., et al. A systematic evaluation of collagen cross-links in the human cervix. Am J Obstet Gynecol. 2015;212:321.e1-321.e8. https://doi.org/10.1016/j.ajog.2014.09.036.

    Article  CAS  PubMed  Google Scholar 

  60. Murphy G, Nagase H. Progress in matrix metalloproteinase research. Mol Aspects Med. 2008;29:290–308. https://doi.org/10.1016/j.mam.2008.05.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Li SY, Yan JQ, Song Z, Liu YF, Song MJ, Qin JW, et al. Molecular characterization of lysyl oxidase-mediated extracellular matrix remodeling during mouse decidualization. FEBS Lett. 2017;591:1394–407. https://doi.org/10.1002/1873-3468.12645.

    Article  CAS  PubMed  Google Scholar 

  62. Fittkow CT, Shi S-Q, Bytautiene E, Olson G, Saade GR, Garfield RE. Changes in light-induced fluorescence of cervical collagen in guinea pigs during gestation and after sodium nitroprusside treatment. J Perinat Med. 2001;29:535–43. https://doi.org/10.1515/JPM.2001.074.

    Article  CAS  PubMed  Google Scholar 

  63. Gunja-Smith Z, Lin J, Woessner JF Jr. Changes in desmosine and pyridinoline crosslinks during rapid synthesis and degradation of elastin and collagen in the rat uterus. Matrix. 1989;9(1):21–7. https://doi.org/10.1016/s0934-8832(89)80014-9.

    Article  CAS  PubMed  Google Scholar 

  64. Glassman W, Byam-Smith M, Garfield RE. Changes in rat cervical collagen during gestation and after antiprogesterone treatment as measured in vivo with light-induced autofluorescence. Am J Obstet Gynecol. 1995;173(5):1550–6. https://doi.org/10.1016/0002-9378(95)90648-7.

    Article  CAS  PubMed  Google Scholar 

  65. Maul H, Olson G, Fittkow CT, Saade GR, Garfield RE. Cervical light-induced fluorescence in humans decreases throughout gestation and before delivery: preliminary observations. Am J Obstet Gynecol. 2003;188:537–41. https://doi.org/10.1067/mob.2003.94.

    Article  PubMed  Google Scholar 

  66. Akins ML, Luby-Phelps K, Bank RA, Mahendroo M. Cervical softening during pregnancy: regulated changes in collagen cross-linking and composition of matricellular proteins in the mouse. Biol Reprod. 2011;84:1053–62. https://doi.org/10.1095/biolreprod.110.089599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Myers K, Socrate S, Tzeranis D, House M. Changes in the biochemical constituents and morphologic appearance of the human cervical stroma during pregnancy. Eur J Obstet Gynecol Reprod Biol. 2009;144:S82–9. https://doi.org/10.1016/j.ejogrb.2009.02.008.

    Article  CAS  PubMed  Google Scholar 

  68. Winkler M, Rath W. Changes in the cervical extracellular matrix during pregnancy and parturition. J Perinat Med. 1999;27(1):45–60. https://doi.org/10.1515/JPM.1999.006.

    Article  CAS  PubMed  Google Scholar 

  69. Mahendroo M. Cervical remodeling in term and preterm birth: insights from an animal model. Reproduction. 2012;143:429–38. https://doi.org/10.1530/REP-11-0466.

    Article  CAS  PubMed  Google Scholar 

  70. Nallasamy S, Palacios HH, Setlem R, Colon Caraballo M, Li K, Cao E, et al. Transcriptome and proteome dynamics of cervical remodeling in the mouse during pregnancy†. Biol Reprod. 2021;105:1257–71. https://doi.org/10.1093/biolre/ioab144.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Uldbjerg N, Ekman G, Malmström A, Olsson K, Ulmsten U. Ripening of the human uterine cervix related to changes in collagen, glycosaminoglycans, and collagenolytic activity. Am J Obstet Gynecol. 1983;147:662–6. https://doi.org/10.1016/0002-9378(83)90446-5.

    Article  CAS  PubMed  Google Scholar 

  72. Buhimschi IA, Dussably L, Buhimschi CS, Ahmed A, Weiner CP. Physical and biomechanical characteristics of rat cervical ripening are not consistent with increased collagenase activity. Am J Obstet Gynecol. 2004;191:1695–704. https://doi.org/10.1016/j.ajog.2004.03.080.

    Article  CAS  PubMed  Google Scholar 

  73. Mahendroo MS, Porter A, Russell DW, Word RA. The parturition defect in steroid 5α-reductase type 1 knockout mice is due to impaired cervical ripening. Mol Endocrinol. 1999;13:981–92. https://doi.org/10.1210/mend.13.6.0307.

    Article  CAS  PubMed  Google Scholar 

  74. Drzewiecki G, Tozzi C, Yu SY, Leppert PC. A dual mechanism of biomechanical change in rat cervix in gestation and postpartum: applied vascular mechanics. Cardiovasc Eng. 2005;5:187–93. https://doi.org/10.1007/s10558-005-9072-z.

    Article  Google Scholar 

  75. Read CP, Word RA, Ruscheinsky MA, Timmons BC, Mahendroo MS. Cervical remodeling during pregnancy and parturition: molecular characterization of the softening phase in mice. Reproduction. 2007;134:327–40. https://doi.org/10.1530/REP-07-0032.

    Article  CAS  PubMed  Google Scholar 

  76. Yoshida K, Jayyosi C, Lee N, Mahendroo M, Myers KM. Mechanics of cervical remodelling: insights from rodent models of pregnancy. Interface Focus. 2019;9:20190026. https://doi.org/10.1098/rsfs.2019.0026.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Shi L, Hu L, Lee N, Fang S, Myers K. Three-dimensional anisotropic hyperelastic constitutive model describing the mechanical response of human and mouse cervix. Acta Biomater. 2022;150:277–94. https://doi.org/10.1016/j.actbio.2022.07.062.

    Article  PubMed  Google Scholar 

  78. Tantengco OAG, Menon R. Contractile function of the cervix plays a role in normal and pathological pregnancy and parturition. Med Hypotheses. 2020;145:110336. https://doi.org/10.1016/j.mehy.2020.110336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Timmons BC, Mahendroo M. Processes regulating cervical ripening differ from cervical dilation and postpartum repair: insights from gene expression studies. Reprod Sci. 2007;14:53–62. https://doi.org/10.1177/1933719107309587.

    Article  CAS  PubMed  Google Scholar 

  80. Zork N, Vink J, Yoshida K, Cremers S, Jiang H, Ananth C, et al. 746: The affect of parity on the distribution of collagen crosslinks in the human cervix. Am J Obstet Gynecol. 2014;210:S366–7. https://doi.org/10.1016/j.ajog.2013.10.779.

    Article  Google Scholar 

  81. Buhimschi C, Buhimschi I, Sharer JD, MacKay L, Diamond M, Weiner C, et al. Labor has no effect on total collagen or collagen cross-links in the lower uterine segment (LUS). Am J Obstet Gynecol. 2003;189:S139. https://doi.org/10.1016/j.ajog.2003.10.283.

    Article  Google Scholar 

  82. Buhimschi CS, Buhimschi IA, Yu C, Wang H, Sharer DJ, Diamond MP, et al. The effect of dystocia and previous cesarean uterine scar on the tensile properties of the lower uterine segment. Am J Obstet Gynecol. 2006;194:873–83. https://doi.org/10.1016/j.ajog.2005.09.004.

    Article  PubMed  Google Scholar 

  83. Stone PJ, Franzblau C. Increase in urinary desmosine and pyridinoline during postpartum involution of the uterus in humans. Exp Biol Med. 1995;210:39–42. https://doi.org/10.3181/00379727-210-43922.

    Article  CAS  Google Scholar 

  84. Kaidi R, Brown PJ, David JS, Etherington DJ, Robins SP. Uterine collagen during involution in cattle. Matrix. 1991;11(2):101–7. https://doi.org/10.1016/s0934-8832(11)80213-1.

    Article  CAS  PubMed  Google Scholar 

  85. Barnum CE, Fey JL, Weiss SN, Barila G, Brown AG, Connizzo BK, et al. Tensile mechanical properties and dynamic collagen fiber re-alignment of the murine cervix are dramatically altered throughout pregnancy. J Biomech Eng. 2017;139:061008. https://doi.org/10.1115/1.4036473.

  86. Bailey A. Molecular mechanisms of ageing in connective tissues. Mech Ageing Dev. 2001;122:735–55. https://doi.org/10.1016/S0047-6374(01)00225-1.

    Article  CAS  PubMed  Google Scholar 

  87. Cannon DJ, Davison PF. Aging, and crosslinking in mammalian collagen. Exp Aging Res. 1977;3:87–105. https://doi.org/10.1080/03610737708257091.

    Article  CAS  PubMed  Google Scholar 

  88. Leppert PC. Cervical softening, effacement, and dilatation: a complex biochemical cascade. J Matern Fetal Neonatal Med. 1992;1(4):213–23. https://doi.org/10.3109/14767059209161921.

    Article  CAS  Google Scholar 

  89. Uldbjerg N, Ulmsten U, Ekman G. The ripening of the human uterine cervix in terms of connective tissue biochemistry. Clin Obstet Gynecol. 1983;26:14–26. https://doi.org/10.1097/00003081-198303000-00006.

    Article  CAS  PubMed  Google Scholar 

  90. Maul H, Shi L, Marx SG, Garfield RE, Saade GR. Local application of platelet-activating factor induces cervical ripening accompanied by infiltration of polymorphonuclear leukocytes in rats. Am J Obstet Gynecol. 2002;187:829–33. https://doi.org/10.1067/mob.2002.126983.

    Article  CAS  PubMed  Google Scholar 

  91. Maul H, Saade G, Garfield RE. Prediction of term and preterm parturition and treatment monitoring by measurement of cervical cross-linked collagen using light-induced fluorescence. Acta Obstet Gynecol Scand. 2005;84:534–6. https://doi.org/10.1111/j.0001-6349.2005.00806.x.

    Article  PubMed  Google Scholar 

  92. Schlembach D, Maul H, Fittkow C, Olson G, Saade G, Garfield R. Cross-linked collagen in the cervix of pregnant women with cervical insufficiency. Am J Obstet Gynecol. 2003;189:S70. https://doi.org/10.1016/j.ajog.2003.10.034.

    Article  Google Scholar 

  93. Etemadi M, Chung P, Heller JA, Liu J, Grossman-Kahn R, Rand L, et al. Novel device to trend impedance and fluorescence of the cervix for preterm birth detection. Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS, 2013, p. 176–179. https://doi.org/10.1109/EMBC.2013.6609466.

  94. Timmons B, Akins M, Mahendroo M. Cervical remodeling during pregnancy and parturition. Trends Endocrinol Metab. 2010;21:353–61. https://doi.org/10.1016/j.tem.2010.01.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chwalisz K. The use of progesterone antagonists for cervical ripening and as an adjunct to labour and delivery. Hum Reprod. 1994;9:131–61. https://doi.org/10.1093/humrep/9.suppl_1.131.

    Article  CAS  PubMed  Google Scholar 

  96. Garfield RE, Gasc JM, Baulieu EE. Effects of the antiprogesterone RU 486 on preterm birth in the rat. Am J Obstet Gynecol. 1987;157:1281–5. https://doi.org/10.1016/S0002-9378(87)80315-0.

    Article  CAS  PubMed  Google Scholar 

  97. Kuon RJ, Shi S-Q, Maul H, Sohn C, Balducci J, Maner WL, et al. Pharmacologic actions of progestins to inhibit cervical ripening and prevent delivery depend on their properties, the route of administration, and the vehicle. Am J Obstet Gynecol. 2010;202:455.e1–9. https://doi.org/10.1016/j.ajog.2010.03.025.

    Article  CAS  PubMed  Google Scholar 

  98. Sato T, Ito A, Mori Y, Yamashita K, Hayakawa T, Nagase H. Hormonal regulation of collagenolysis in uterine cervical fibroblasts. Modulation of synthesis of procollagenase, prostromelysin and tissue inhibitor of metalloproteinases (TIMP) by progesterone and oestradiol-17 β. Biochemical J. 1991;275:645–50. https://doi.org/10.1042/bj2750645.

    Article  CAS  Google Scholar 

  99. House M, Kelly J, Klebanov N, Yoshida K, Myers K, Kaplan DL. Mechanical and biochemical effects of progesterone on engineered cervical tissue. Tissue Eng Part A. 2018;24:1765–74. https://doi.org/10.1089/ten.tea.2018.0036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Itoh H, Keller P, Word RA. Effect of estradiol and transforming growth factor beta 1(TGFβ1) on expression of lysyl oxidase(LOX) in three-dimensional (3D) cocultures of human endometrium. Fertil Steril. 2011;96:S146. https://doi.org/10.1016/j.fertnstert.2011.07.568.

    Article  Google Scholar 

  101. Tamada H, Shimizu Y, Inaba T, Kawate N, Sawada T. The effects of the aromatase inhibitor fadrozole hydrochloride on fetuses and uteri in late pregnant rats. J Endocrinol. 2004;180(2):337–45. https://doi.org/10.1677/joe.0.1800337.

    Article  CAS  PubMed  Google Scholar 

  102. Jeffrey J, Coffey R, Eisen A. Studies on uterine collagenase in tissue cultureII. Effect of steroid hormones on enzyme production. Biochim Biophys Acta Gen Subj. 1971;252:143–9. https://doi.org/10.1016/0304-4165(71)90102-4.

    Article  CAS  Google Scholar 

  103. Reeves CV, Wang X, Charles-Horvath PC, Vink JY, Borisenko VY, Young JAT, et al. Anthrax toxin receptor 2 functions in ECM homeostasis of the murine reproductive tract and promotes MMP activity. PLoS One. 2012;7:e34862. https://doi.org/10.1371/journal.pone.0034862.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  104. Hajabi MR, Solomon S, Robin PA. Biochemical evidence of collagenase-mediated collagenolysis as a mechanism of cervical dilatation at parturition in the guinea pig. Biol Reprod. 1991;45:764–72. https://doi.org/10.1095/biolreprod45.5.764.

    Article  Google Scholar 

  105. Osmers R, Rath W, Adelmann-Grill BC, Fittkow C, Severényi M, Kuhn W. Collagenase activity in the cervix of non-pregnant and pregnant women. Arch Gynecol Obstet. 1990;248:75–80. https://doi.org/10.1007/BF02389578.

    Article  CAS  PubMed  Google Scholar 

  106. Rath W, Adelmann-Grill BC, Osmers R, Kuhn W. Enzymatic collagen degradation in the pregnant guinea pig cervix during physiological maturation of the cervix and after local application of prostaglandins. Eur J Obstet Gynecol Reprod Biol. 1989;32:199–204. https://doi.org/10.1016/0028-2243(89)90036-1.

    Article  CAS  PubMed  Google Scholar 

  107. Vink J, Yu V, Dahal S, Lohner J, Stern-Asher C, Mourad M, et al. Extracellular matrix rigidity modulates human cervical smooth muscle contractility—new insights into premature cervical failure and spontaneous preterm birth. Reprod Sci. 2021;28:237–51. https://doi.org/10.1007/s43032-020-00268-6.

    Article  CAS  PubMed  Google Scholar 

  108. Yellon SM, Greaves E, Heuerman AC, Dobyns AE, Norman JE. Effects of macrophage depletion on characteristics of cervix remodeling and pregnancy in CD11b-dtr mice. Biol Reprod. 2019;100:1386–94. https://doi.org/10.1093/biolre/ioz002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Yellon SM, Ebner CA, Elovitz MA. Medroxyprogesterone acetate modulates remodeling, immune cell census, and nerve fibers in the cervix of a mouse model for inflammation-induced preterm birth. Reprod Sci. 2009;16:257–64. https://doi.org/10.1177/1933719108325757.

    Article  CAS  PubMed  Google Scholar 

  110. Ng MR, Brugge JS. A stiff blow from the stroma: collagen crosslinking drives tumor progression. Cancer Cell. 2009;16:455–7. https://doi.org/10.1016/j.ccr.2009.11.013.

    Article  CAS  PubMed  Google Scholar 

  111. Endo T, Kiya T, Goto T, Henmi H, Manase K, Honnma H, et al. Significance of matrix metalloproteinases in the pathophysiology of the ovary and uterus. Reprod Med Biol. 2006;5:235–43. https://doi.org/10.1111/j.1447-0578.2006.00147.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Rechberger T, Woessner JF. Collagenase, its inhibitors, and decorin in the lower uterine segment in pregnant women. Am J Obstet Gynecol. 1993;168:1598–603. https://doi.org/10.1016/S0002-9378(11)90804-7.

    Article  CAS  PubMed  Google Scholar 

  113. Lyons CA, Beharry KD, Nishihara KC, Akmal Y, Ren ZY, Chang E, et al. Regulation of matrix metalloproteinases (type IV collagenases) and their inhibitors in the virgin, timed pregnant, and postpartum rat uterus and cervix by prostaglandin E2-cyclic adenosine monophosphate. Am J Obstet Gynecol. 2002;187:202–8. https://doi.org/10.1067/mob.2002.123543.

    Article  CAS  PubMed  Google Scholar 

  114. Rath W, Adelmann-Grill BC, Pieper U, Kuhn W. Collagen degradation in the pregnant human cervix at term and after prostaglandin-induced cervical ripening. Arch Gynecol. 1987;240:177–84. https://doi.org/10.1007/BF00207713.

    Article  CAS  PubMed  Google Scholar 

  115. Uldbjerg N. Cervical connective tissue in relation to pregnancy, labour, and treatment with prostaglandin E 2. Acta Obstet Gynecol Scand. 1989;68:1–40. https://doi.org/10.3109/00016348909156497.

    Article  Google Scholar 

  116. Osmers R, Rath W, Adelmann-Grill BC, Fittkow C, Kuloczik M, Szeverényi M, et al. Origin of cervical collagenase during parturition. Am J Obstet Gynecol. 1992;166:1455–60. https://doi.org/10.1016/0002-9378(92)91619-L.

    Article  CAS  PubMed  Google Scholar 

  117. Osmers R, Rath W, Adelmann-Grill BC, Fittkow C, Szeverényi M, Kuhn W. Collagenase activity in the human cervix uteri after prostaglandin E2 application during the first trimester. Eur J Obstet Gynecol Reprod Biol. 1991;42(1):29–32. https://doi.org/10.1016/0028-2243(91)90155-e.

    Article  CAS  PubMed  Google Scholar 

  118. Fittkow CT, Maul H, Olson G, Martin E, MacKay LB, Saade GR, et al. Light-induced fluorescence of the human cervix decreases after prostaglandin application for induction of labor at term. Eur J Obstet Gynecol Reprod Biol. 2005;123:62–6. https://doi.org/10.1016/j.ejogrb.2005.03.006.

    Article  CAS  PubMed  Google Scholar 

  119. Feltovich H, Ji H, Janowski JW, Delance NC, Moran CC, Chien EK. Effects of selective and nonselective PGE2 receptor agonists on cervical tensile strength and collagen organization and microstructure in the pregnant rat at term. Am J Obstet Gynecol. 2005;192:753–60. https://doi.org/10.1016/j.ajog.2004.12.054.

    Article  CAS  PubMed  Google Scholar 

  120. Pastore GN, DiCola LP, Dollahon NR, Gardner RM. The effect of estradiol on collagen structure and organization in the immature rat uterus. Exp Biol Med. 1989;191:69–77. https://doi.org/10.3181/00379727-191-42891.

    Article  CAS  Google Scholar 

  121. Lee N, Shi L, Colon Caraballo M, Nallasamy S, Mahendroo M, Iozzo R v., et al. Mechanical response of mouse cervices lacking decorin and biglycan during pregnancy. J Biomech Eng. 2022;144:061009. https://doi.org/10.1115/1.4054199.

  122. Colon-Caraballo M, Lee N, Nallasamy S, Myers K, Hudson D, Iozzo R v., et al. Novel regulatory roles of small leucine-rich proteoglycans in remodeling of the uterine cervix in pregnancy. Matrix Biol. 2022;105:53–71. https://doi.org/10.1016/j.matbio.2021.11.004.

    Article  CAS  PubMed  Google Scholar 

  123. Antoniotti GS, Coughlan M, Salamonsen LA, Evans J. Obesity associated advanced glycation end products within the human uterine cavity adversely impact endometrial function and embryo implantation competence. Hum Reprod. 2018;33:654–65. https://doi.org/10.1093/humrep/dey029.

    Article  CAS  PubMed  Google Scholar 

  124. Hutchison JC, Truong TT, Salamonsen LA, Gardner DK, Evans J. Advanced glycation end products present in the obese uterine environment compromise preimplantation embryo development. Reprod Biomed Online. 2020;41:757–66. https://doi.org/10.1016/j.rbmo.2020.07.026.

    Article  CAS  PubMed  Google Scholar 

  125. Dubicke A, Andersson P, Fransson E, Andersson E, Sioutas A, Malmström A, et al. High-mobility group box protein 1 and its signalling receptors in human preterm and term cervix. J Reprod Immunol. 2010;84:86–94. https://doi.org/10.1016/j.jri.2009.09.010.

    Article  CAS  PubMed  Google Scholar 

  126. You L, Cui H, Zhao F, Sun H, Zhong H, Zhou G, et al. Inhibition of HMGB1/RAGE axis suppressed the lipopolysaccharide (LPS)-induced vicious transformation of cervical epithelial cells. Bioengineered. 2021;12:4995–5003. https://doi.org/10.1080/21655979.2021.1957750.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Shi L, Shi S-Q, Saade GR, Chwalisz K, Garfield RE. Changes in cervical resistance and collagen fluorescence during gestation in rats. J Perinat Med. 1999;27:188–94. https://doi.org/10.1515/JPM.1999.026.

    Article  CAS  PubMed  Google Scholar 

  128. Yang J, Shi SQ, Shi L, Liu H, Fang D, Garfield RE. Nicotine treatment prolongs gestation and inhibits cervical ripening in pregnant rats. Am J Obstet Gynecol. 2014;210:76.e1–7. https://doi.org/10.1016/j.ajog.2013.09.012.

    Article  CAS  PubMed  Google Scholar 

  129. MacKay LB, Shi L, Maul H, Maner WL, Garfield RE. The effect of bilateral pelvic neurectomy on cervical ripening in pregnant rats. J Perinat Med. 2009;37:263–9. https://doi.org/10.1515/JPM.2009.043.

    Article  PubMed  Google Scholar 

  130. Maul H, Mackay L, Garfield RE. Cervical ripening: biochemical, molecular, and clinical considerations. Clin Obstet Gynecol. 2006;49:551–63. https://doi.org/10.1097/00003081-200609000-00015.

    Article  PubMed  Google Scholar 

  131. Cramer SF, Patel A. The frequency of uterine leiomyomas. Am J Clin Pathol. 1990;94:435–8. https://doi.org/10.1093/ajcp/94.4.435.

    Article  CAS  PubMed  Google Scholar 

  132. Leppert PC, Baginski T, Prupas C, Catherino WH, Pletcher S, Segars JH. Comparative ultrastructure of collagen fibrils in uterine leiomyomas and normal myometrium. Fertil Steril. 2004;82:1182–7. https://doi.org/10.1016/j.fertnstert.2004.04.030.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Malik M, Norian J, McCarthy-Keith D, Britten J, Catherino W. Why leiomyomas are called fibroids: the central role of extracellular matrix in symptomatic women. Semin Reprod Med. 2010;28:169–79. https://doi.org/10.1055/s-0030-1251475.

    Article  PubMed  Google Scholar 

  134. van der Slot AJ, van Dura EA, de Wit EC, DeGroot J, Huizinga TWJ, Bank RA, et al. Elevated formation of pyridinoline cross-links by profibrotic cytokines is associated with enhanced lysyl hydroxylase 2b levels. Biochim Biophys Acta Mol Basis Dis. 2005;1741:95–102. https://doi.org/10.1016/j.bbadis.2004.09.009.

    Article  CAS  Google Scholar 

  135. López B, González A, Hermida N, Valencia F, de Teresa E, Díez J. Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects. Am J Physiol Heart Circ Physiol. 2010;299:H1–9. https://doi.org/10.1152/ajpheart.00335.2010.

    Article  CAS  PubMed  Google Scholar 

  136. Wells RG. The role of matrix stiffness in regulating cell behavior. Hepatology. 2008;47:1394–400. https://doi.org/10.1002/hep.22193.

    Article  CAS  PubMed  Google Scholar 

  137. Kamel M, Wagih M, Kilic GS, Diaz-Arrastia CR, Baraka MA, Salama SA. Overhydroxylation of lysine of collagen increases uterine fibroids proliferation: roles of lysyl hydroxylases, lysyl oxidases, and matrix metalloproteinases. Biomed Res Int. 2017;2017:5316845. https://doi.org/10.1155/2017/5316845.

  138. Stewart EA, Friedman AJ, Peck K, Nowak RA. Relative overexpression of collagen type I and collagen type III messenger ribonucleic acids by uterine leiomyomas during the proliferative phase of the menstrual cycle. J Clin Endocrinol Metab. 1994;79:900–6. https://doi.org/10.1210/jcem.79.3.8077380.

    Article  CAS  PubMed  Google Scholar 

  139. Seth P, Yeowell HN. Fox-2 protein regulates the alternative splicing of scleroderma-associated lysyl hydroxylase 2 messenger RNA. Arthritis Rheum. 2010;62:1167–75. https://doi.org/10.1002/art.27315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. van der Slot AJ, Zuurmond A-M, Bardoel AFJ, Wijmenga C, Pruijs HEH, Sillence DO, et al. Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis. J Biol Chem. 2003;278:40967–72. https://doi.org/10.1074/jbc.M307380200.

    Article  CAS  PubMed  Google Scholar 

  141. Trackman PC. Lysyl oxidase isoforms and potential therapeutic opportunities for fibrosis and cancer. Expert Opin Ther Targets. 2016;20:935–45. https://doi.org/10.1517/14728222.2016.1151003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Cox TR, Bird D, Baker AM, Barker HE, Ho MWY, Lang G, et al. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res. 2013;73:1721–32. https://doi.org/10.1158/0008-5472.CAN-12-2233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Chegini N, Tang X-M, Ma C. Regulation of transforming growth factor-β1 expression by granulocyte macrophage-colony-stimulating factor in leiomyoma and myometrial smooth muscle cells. J Clin Endocrinol Metab. 1999;84:4138–43. https://doi.org/10.1210/jcem.84.11.6147.

    Article  CAS  PubMed  Google Scholar 

  144. Desmoulière A, Chaponnier C, Gabbiani G. Tissue repair, contraction, and the myofibroblast. Wound Repair and Regen. 2005;13:7–12. https://doi.org/10.1111/j.1067-1927.2005.130102.x.

    Article  Google Scholar 

  145. Majora M, Wittkampf T, Schuermann B, Schneider M, Franke S, Grether-Beck S, et al. Functional consequences of mitochondrial DNA deletions in human skin fibroblasts. Am J Pathol. 2009;175:1019–29. https://doi.org/10.2353/ajpath.2009.080832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Uzumcu M. Localization of connective tissue growth factor in human uterine tissues. Mol Hum Reprod. 2000;6:1093–8. https://doi.org/10.1093/molehr/6.12.1093.

    Article  CAS  PubMed  Google Scholar 

  147. Ohashi S, Abe H, Takahashi T, Yamamoto Y, Takeuchi M, Arai H, et al. Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy. J Biol Chem. 2004;279:19816–23. https://doi.org/10.1074/jbc.M310428200.

    Article  CAS  PubMed  Google Scholar 

  148. Brinckmann J, Tronnier M, Schmeller W, Notbohm H, Açil Y, Fietzek PP, et al. Overhydroxylation of lysyl residues is the initial step for altered collagen cross-links and fibril architecture in fibrotic skin. J Invest Dermatol. 1999;113:617–21. https://doi.org/10.1046/j.1523-1747.1999.00735.x.

    Article  CAS  PubMed  Google Scholar 

  149. Ruotsalainen H, Sipilä L, Vapola M, Sormunen R, Salo AM, Uitto L, et al. Glycosylation catalyzed by lysyl hydroxylase 3 is essential for basement membranes. J Cell Sci. 2006;119:625–35. https://doi.org/10.1242/jcs.02780.

    Article  CAS  PubMed  Google Scholar 

  150. Korompelis P, Piperi C, Adamopoulos C, Dalagiorgou G, Korkolopoulou P, Sepsa A, et al. Expression of vascular endothelial factor-A, gelatinases (MMP-2, MMP-9) and TIMP-1 in uterine leiomyomas. Clin Chem Lab Med. 2015;53:1415–24. https://doi.org/10.1515/cclm-2014-0798.

    Article  CAS  PubMed  Google Scholar 

  151. Halder SK, Osteen KG, Al-Hendy A. Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and -9 in human uterine fibroid cells. Hum Reprod. 2013;28:2407–16. https://doi.org/10.1093/humrep/det265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Islam MS, Ciavattini A, Petraglia F, Castellucci M, Ciarmela P. Extracellular matrix in uterine leiomyoma pathogenesis: a potential target for future therapeutics. Hum Reprod Update. 2018;24:59–85. https://doi.org/10.1093/humupd/dmx032.

    Article  CAS  PubMed  Google Scholar 

  153. Islam MS, Protic O, Giannubilo SR, Toti P, Tranquilli AL, Petraglia F, et al. Uterine leiomyoma: available medical treatments and new possible therapeutic options. J Clin Endocrinol Metab. 2013;98:921–34. https://doi.org/10.1210/jc.2012-3237.

    Article  CAS  PubMed  Google Scholar 

  154. Guo HF, Cho EJ, Devkota AK, Chen Y, Russell W, Phillips GN, et al. A scalable lysyl hydroxylase 2 expression system and luciferase-based enzymatic activity assay. Arch Biochem Biophys. 2017;618:45–51. https://doi.org/10.1016/j.abb.2017.02.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Vallet SD, Ricard-Blum S. Lysyl oxidases: From enzyme activity to extracellular matrix cross-links. Essays Biochem. 2019;63:349–64. https://doi.org/10.1042/EBC20180050.

    Article  CAS  PubMed  Google Scholar 

  156. Zhang C, Ma J, Wang W, Sun Y, Sun K. Lysyl oxidase blockade ameliorates anovulation in polycystic ovary syndrome. Hum Reprod. 2018;33:2096–106. https://doi.org/10.1093/humrep/dey292.

    Article  CAS  PubMed  Google Scholar 

  157. Henmi H, Endo T, Nagasawa K, Hayashi T, Chida M, Akutagawa N, Iwasaki M, Kitajima Y, Kiya T, Nishikawa A, Manase K, Kudo R. Lysyl oxidase and MMP-2 expression in dehydroepiandrosterone-induced polycystic ovary in rats. Biol Reprod. 2001;64(1):157–62. https://doi.org/10.1095/biolreprod64.1.157.

    Article  CAS  PubMed  Google Scholar 

  158. Harlow CR, Rae M, Davidson L, Trackman PC, Hillier SG. Lysyl oxidase gene expression and enzyme activity in the rat ovary: regulation by follicle-stimulating hormone, androgen, and transforming growth factor-β superfamily members in vitro. Endocrinology. 2003;144:154–62. https://doi.org/10.1210/en.2002-220652.

    Article  CAS  PubMed  Google Scholar 

  159. Jayes FL, Liu B, Moutos FT, Kuchibhatla M, Guilak F, Leppert PC. Loss of stiffness in collagen-rich uterine fibroids after digestion with purified collagenase Clostridium histolyticum. Am J Obstet Gynecol. 2016;215:e1-596.e8. https://doi.org/10.1016/j.ajog.2016.05.006.

    Article  CAS  Google Scholar 

  160. Matsuzaki S, Canis M, Darcha C, Dechelotte P, Pouly J-L, MauriceA B. Fibrogenesis in Peritoneal Endometriosis. Gynecol Obstet Invest. 1999;47:197–9. https://doi.org/10.1159/000010094.

    Article  CAS  PubMed  Google Scholar 

  161. Garcia Garcia JM, Vannuzzi V, Donati C, Bernacchioni C, Bruni P, Petraglia F. Endometriosis: cellular and molecular mechanisms leading to fibrosis. Reprod Sci. 2023;30:1453–61. https://doi.org/10.1007/s43032-022-01083-x.

    Article  PubMed  Google Scholar 

  162. Konno R, Fujiwara H, Netsu S, Odagiri K, Shimane M, Nomura H, et al. Gene expression profiling of the rat endometriosis model. Am J Reprod Immunol. 2007;58:330–43. https://doi.org/10.1111/j.1600-0897.2007.00507.x.

    Article  CAS  PubMed  Google Scholar 

  163. Horne AW, Missmer SA. Pathophysiology, diagnosis, and management of endometriosis. BMJ. 2022;379:e070750. https://doi.org/10.1136/bmj-2022-070750.

  164. Flores I, Rivera E, Ruiz LA, Santiago OI, Vernon MW, Appleyard CB. Molecular profiling of experimental endometriosis identified gene expression patterns in common with human disease. Fertil Steril. 2007;87:1180–99. https://doi.org/10.1016/j.fertnstert.2006.07.1550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Wilson MR, Reske JJ, Chandler RL. AP-1 Subunit JUNB promotes invasive phenotypes in endometriosis. Reprod Sci. 2022;29:3266–77. https://doi.org/10.1007/s43032-022-00974-3.

    Article  CAS  PubMed  Google Scholar 

  166. Ruiz LA, Báez-Vega PM, Ruiz A, Peterse DP, Monteiro JB, Bracero N, et al. Dysregulation of lysyl oxidase expression in lesions and endometrium of women with endometriosis. Reprod. Sci. 2015;22:1496–508. https://doi.org/10.1177/1933719115585144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Eyster KM, Klinkova O, Kennedy V, Hansen KA. Whole genome deoxyribonucleic acid microarray analysis of gene expression in ectopic versus eutopic endometrium. Fertil Steril. 2007;88:1505–33. https://doi.org/10.1016/j.fertnstert.2007.01.056.

    Article  CAS  PubMed  Google Scholar 

  168. Savaris RF, Hamilton AE, Lessey BA, Giudice LC. Endometrial gene expression in early pregnancy: lessons from human ectopic pregnancy. Reprod Sci. 2008;15:797–816. https://doi.org/10.1177/1933719108317585.

    Article  CAS  PubMed  Google Scholar 

  169. Flores I, Rivera E, Mousses S, Chen Y, Rozenblum E. Identification of molecular markers for endometriosis in blood lymphocytes by using deoxyribonucleic acid microarrays. Fertil Steril. 2006;85:1676–83. https://doi.org/10.1016/j.fertnstert.2005.11.076.

    Article  CAS  PubMed  Google Scholar 

  170. Dentillo DB, Meola J, Rosa Silva JC, Giuliatti S, Silva WA, Ferriani RA, et al. Deregulation of LOXL1 and HTRA1 gene expression in endometriosis. Reprod Sci. 2010;17:1016–23. https://doi.org/10.1177/1933719110377662.

    Article  CAS  PubMed  Google Scholar 

  171. Ruiz LA, Dutil J, Ruiz A, Fourquet J, Abac S, Laboy J, et al. Single-nucleotide polymorphisms in the lysyl oxidase-like protein 4 and complement component 3 genes are associated with increased risk for endometriosis and endometriosis-associated infertility. Fertil Steril. 2011;96:512–5. https://doi.org/10.1016/j.fertnstert.2011.06.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Painter JN, Nyholt DR, Morris A, Zhao ZZ, Henders AK, Lambert A, et al. High-density fine-mapping of a chromosome 10q26 linkage peak suggests association between endometriosis and variants close to CYP2C19. Fertil Steril. 2011;95:2236–40. https://doi.org/10.1016/j.fertnstert.2011.03.062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Liu X, Shen M, Qi Q, Zhang H, Guo S-W. Corroborating evidence for platelet-induced epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis. Hum Reprod. 2016;31:734–49. https://doi.org/10.1093/humrep/dew018.

    Article  CAS  PubMed  Google Scholar 

  174. Wang S, Li B, Duan H, Wang Y, Shen X, Dong Q. Abnormal expression of connective tissue growth factor and its correlation with fibrogenesis in adenomyosis. Reprod Biomed Online. 2021;42:651–60. https://doi.org/10.1016/j.rbmo.2020.11.002.

    Article  CAS  PubMed  Google Scholar 

  175. Kay N, Huang C-Y, Shiu L-Y, Yu Y-C, Chang Y, Schatz F, et al. TGF-β1 neutralization improves pregnancy outcomes by restoring endometrial receptivity in mice with adenomyosis. Reprod Sci. 2021;28:877–87. https://doi.org/10.1007/s43032-020-00308-1.

    Article  CAS  PubMed  Google Scholar 

  176. Hossain MM, Nakayama K, Shanta K, Razia S, Ishikawa M, Ishibashi T, et al. Establishment of a novel in vitro model of endometriosis with oncogenic KRAS and PIK3CA mutations for understanding the underlying biology and molecular pathogenesis. Cancers (Basel). 2021;13:3174. https://doi.org/10.3390/cancers13133174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Bulun SE, Cheng Y-H, Yin P, Imir G, Utsunomiya H, Attar E, et al. Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol Cell Endocrinol. 2006;248:94–103. https://doi.org/10.1016/j.mce.2005.11.041.

    Article  CAS  PubMed  Google Scholar 

  178. Inagaki N, Ung L, Otani T, Wilkinson D, Lopata A. Uterine cavity matrix metalloproteinases and cytokines in patients with leiomyoma, adenomyosis or endometrial polyp. Eur J Obstet Gynecol Reprod Biol. 2003;111:197–203. https://doi.org/10.1016/S0301-2115(03)00244-6.

    Article  CAS  PubMed  Google Scholar 

  179. Lee J, Banu SK, Subbarao T, Starzinski-Powitz A, Arosh JA. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 inhibits invasion of human immortalized endometriotic epithelial and stromal cells through suppression of metalloproteinases. Mol Cell Endocrinol. 2011;332:306–13. https://doi.org/10.1016/j.mce.2010.11.022.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Irem Kurt & Mostafa A. Borahay

  2. Selcuk University Faculty of Medicine, 42000, Konya, Turkey

    Irem Kurt

  3. Department of Gynecology and Obstetrics, Selcuk University Faculty of Medicine, 42000, Konya, Turkey

    Mehmet Kulhan

  4. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA

    Abdelrahman AlAshqar

Authors
  1. Irem Kurt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mehmet Kulhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abdelrahman AlAshqar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mostafa A. Borahay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mostafa A. Borahay.

Ethics declarations

Ethics Approval

Ethical approval was not required as no human participants or animal models were included.

Competing Interest

Authors have no competing interests to declare.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kurt, I., Kulhan, M., AlAshqar, A. et al. Uterine Collagen Cross-Linking: Biology, Role in Disorders, and Therapeutic Implications. Reprod. Sci. 31, 645–660 (2024). https://doi.org/10.1007/s43032-023-01386-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-023-01386-7

Keywords

Search

Navigation