Relaxin Positively Regulates Matrix Metalloproteinase Expression in Human Lower Uterine Segment Fibroblasts Using a Tyrosine Kinase Signaling Pathway

Abstract

Despite the importance of relaxin to normal parturition in various species and its potential as an etiological agent in preterm delivery in women, knowledge regarding the mechanisms by which relaxin alters cervical connective tissue is extremely limited. An established in vitro model for human pregnancy cervix, human lower uterine segment fibroblasts, was used to determine the effects of relaxin as well as those of progesterone on the expression of matrix metalloproteinases and tissue inhibitor of metalloproteinase-1. The results demonstrate that relaxin is a positive regulator of matrix metalloproteinase expression, as it stimulates the expression of procollagenase protein and mRNA levels, stimulates prostromelysin-1 protein and mRNA levels, and inhibits tissue inhibitor of metalloproteinase-1 protein expression. Stimulation of procollagenase and prostromelysin-1 expression by relaxin does not involve phorbol-12-myristate-13-acetate- sensitive PKCs. Relaxin-stimulated tyrosine phosphorylation of the putative receptor and inhibition by a receptor tyrosine kinase inhibitor suggest that the relaxin receptor is probably a tyrosine kinase receptor. Inhibition of c-Raf protein expression using an antisense oligonucleotide inhibits relaxin regulation of matrix metalloproteinase and tissue inhibitor of metalloproteinase-1, suggesting that a signaling pathway involving c-Raf kinase mediates relaxin action.

Relaxin and gonadal steroid receptors in uterosacral ligaments of women with and without pelvic organ prolapse

“…In view of those results, our findings of regular LGR7 expression in USL SMC and stromal cells may also contribute to the understanding of loss of ligamental resilience via presumable stromal remodeling effects and decreased contractility of SMCs. The known upregulated activity of matrix metalloproteinases in USL of women affected by POP [32] can also be triggered by incubation with relaxin in human lower uterine fibroblasts [33].…”

Relaxin: a pregnancy hormone as central player of body fluid and circulation homeostasis

“…However, evidence is accumulating that the extracellular signal-regulated kinase-1/2 cascade (p42/44 MAP kinase) represents a key mediator of relaxin action. This was demonstrated in human endometrial stromal cells and in the human monocytic cell line THP-1 [93], as well as in human uterine fibroblasts [13]. Undoubtedly, much will emerge from this rapidly evolving field of research in the next few years.…”

“…Proof of cAMP as a pivotal and abundant messenger of relaxin actions also emerged from the field of brain research by Cronin and co-workers [82] who conducted experiments in anterior pituitary cells and from cardiovascular reports by Toth and co-workers [83] describing relaxin-mediated release of atrial natriuretic peptide in rat hearts, as well as by Piedras-Renteria and co-workers [84] who elucidated the positive inotropic effect of relaxin on rat atrial myocytes. Bartsch and co-workers [85] demonstrated in human endometrial stromal cells and in the human monocytic cell line THP-1 that the G-protein-coupled relaxin receptor also initiates tyrosine kinase activation, which has long been advocated [13,75]: the results of these authors imply that activation of the relaxin receptor leads to tyrosine phosphorylation, which, in turn, inhibits phosphodiesterase activity and further upregulates cAMP levels. In 1994, Masini and co-workers [86] were the first to discover a substantially novel mechanism of action of relaxin.…”

“…Two G-protein-coupled receptors were finally identified as the elusive relaxin receptors [11], the gripping mode of which is now also known in detail [12]. Investigation of the signaling pathways of relaxin gained great momentum [13,14], and human relaxin H3 -a new member of the relaxin familiy -was discovered [15]. This review will focus on the recent progress, with particular attention being paid to the versatile effects that relaxin exerts apart from being a hormone of reproduction.…”

Drugs of the future: the hormone relaxin

“…These combined actions of relaxin lead to improved organ repair and function (see text for further details). pulmonary [52], uterine [53] and renal [54] fibroblasts, in addition to rat hepatic stellate cells [55,56] and renal [57], atrial and ventricular fibroblasts [44] (Fig. 4).…”