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

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...

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Published in:Reproductive sciences (Thousand Oaks, Calif.) Calif.), 2024-03, Vol.31 (3), p.645-660
Main Authors: Kurt, Irem, Kulhan, Mehmet, AlAshqar, Abdelrahman, Borahay, Mostafa A.
Format: Article
Language:English
Subjects:
Biology
Cervix Uteri
Collagen
Embryology
Female
Humans
Infant, Newborn
Leiomyoma
Medicine
Medicine & Public Health
Obstetrics/Perinatology/Midwifery
Pregnancy
Premature Birth
Reproductive Medicine
Review
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Summary: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.
ISSN:1933-7191
1933-7205
1933-7205
DOI:10.1007/s43032-023-01386-7