Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Selcuk University Faculty of Medicine, 42000, Konya, Turkey.
Reprod Sci. 2024 Mar;31(3):645-660. doi: 10.1007/s43032-023-01386-7. Epub 2023 Oct 31.
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.
胶原蛋白是子宫细胞外基质的重要组成部分，为子宫提供生物力学强度、弹性、结构完整性和正常功能所需的拉伸特性。交联是胶原蛋白生物合成的基本步骤，对其正常的生物物理特性至关重要。这一步通过赖氨酰氧化酶 (LOX) 或非酶促反应，通过产生晚期糖基化终产物 (AGEs) 来完成。在子宫组织中发现的交联包括可还原的脱氢二羟赖氨酰正亮氨酸 (deH-DHLNL)、脱氢羟赖氨酰正亮氨酸 (deH-HLNL) 和组氨酰羟赖氨酰脱甲酰基赖氨酸 (HHMD)；以及不可还原的吡啶啉 (PYD)、脱氧吡啶啉 (DPD)；和微量的戊糖胺 (PEN)。胶原蛋白交联对于子宫组织完整性和健康妊娠的延续至关重要。早产时观察到宫颈交联密度降低，而交联密度增加导致的组织僵硬是子宫肌瘤的致病特征。AGEs 会破坏胚胎发育、蜕膜化、着床和滋养细胞浸润。调节子宫胶原蛋白交联的因素包括甾体激素，如孕酮和雌激素、前列腺素、蛋白聚糖、金属蛋白酶、赖氨酰氧化酶、一氧化氮、尼古丁和维生素 D。因此，子宫胶原蛋白交联为设计治疗靶点提供了机会，并值得在常见的子宫疾病（如子宫肌瘤、宫颈机能不全、早产、难产、子宫内膜异位症和子宫腺肌病）中进一步研究。
