Colon-Caraballo Mariano, Russell Serena R, Myers Kristin M, Mahendroo Mala
Department of Ob/Gyn and Cecil H. and Ida Green Center for Reproductive Biology Sciences, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Department of Mechanical Engineering, Columbia University, New York, New York City, United States of America.
Biol Reprod. 2025 Apr 13;112(4):709-727. doi: 10.1093/biolre/ioaf012.
Reproductive success requires accurately timed remodeling of the cervix to orchestrate the maintenance of pregnancy, the process of labor, and birth. Prior work in mice established that a combination of continuous turnover of fibrillar collagen and reduced formation of collagen cross-links allows for the gradual increase in tissue compliance and delivery of the fetus during labor. However, the mechanism for continuous collagen degradation to ensure turnover during cervical remodeling is still unknown. This study demonstrates the functional role of extracellular and intracellular collagen degradative pathways in two different settings of cervical remodeling: physiological term remodeling and inflammation-mediated premature remodeling. Extracellular collagen degradation is achieved by the activity of fibroblast-derived matrix metalloproteases MMP14, MMP2, and fibroblast activation protein (FAP). In parallel, we demonstrate the function of an intracellular collagen degradative pathway in fibroblast cells mediated by the collagen endocytic mannose receptor type-2 (MRC2). These pathways appear to be functionally redundant as loss of MRC2 does not obstruct collagen turnover or cervical function in pregnancy. While both extracellular and intracellular pathways are also utilized in inflammation-mediated premature cervical remodeling, the extracellular collagen degradation pathway uniquely employs fibroblast and immune-cell-derived proteases. In sum, these findings identify the dual utilization of two distinct degradative pathways as a failsafe mechanism to achieve continuous collagen turnover in the cervix, thereby allowing dynamic shifts in cervical tissue mechanics and function.
生殖成功需要子宫颈进行精确的适时重塑，以协调维持妊娠、分娩过程和生产。先前在小鼠身上的研究表明，原纤维胶原蛋白的持续更新与胶原蛋白交联形成减少相结合，使得组织顺应性逐渐增加，并在分娩时实现胎儿的娩出。然而，在子宫颈重塑过程中确保胶原蛋白持续更新的胶原蛋白降解机制仍不清楚。本研究证明了细胞外和细胞内胶原蛋白降解途径在子宫颈重塑的两种不同情况下的功能作用：生理性足月重塑和炎症介导的早产重塑。细胞外胶原蛋白降解是通过成纤维细胞衍生的基质金属蛋白酶MMP14、MMP2和成纤维细胞活化蛋白（FAP）的活性来实现的。同时，我们证明了由胶原蛋白内吞甘露糖受体2型（MRC2）介导的成纤维细胞内胶原蛋白降解途径的功能。这些途径在功能上似乎是冗余的，因为MRC2的缺失并不妨碍妊娠期间的胶原蛋白更新或子宫颈功能。虽然细胞外和细胞内途径也用于炎症介导的子宫颈早产重塑，但细胞外胶原蛋白降解途径独特地利用了成纤维细胞和免疫细胞衍生的蛋白酶。总之，这些发现确定了两种不同降解途径的双重利用是一种故障安全机制，以实现子宫颈中胶原蛋白的持续更新，从而允许子宫颈组织力学和功能的动态变化。
