Greater presence of receptors for relaxin in the ligamentum teres of female infants who undergo open reduction for developmental dysplasia of the hip

Background While many factors involved in the etiology of developmental dysplasia of the hip (DDH), one of which is the hormone relaxin. Relaxin concentrations in patients with DDH may lead to pathodynamic changes during hip development by altering the physiological nature of the ligament, as well as by long-term exposure to relaxin during pregnancy. Our objective in this study was to determine the number of relaxin receptors in the ligamentum teres and their role in causing DDH. Methods We identified 26 infants between birth and 3 years of age who had undergone open reduction for DDH between 2010 and 2012. 12 hips of 12 miss abortus fetus between 20 to 35 weeks of gestation were used as control group. Specimens obtained from two groups were stained with Relaxin-2 antibody, and the amount of staining for relaxin receptors was determined using an ordinal H score. Results The mean (SD) H scores of infants with DDH were significantly higher than those of controls: 215 (59) versus 52 (48); P = 0.00; 95% CI. Statistically significant difference between the two groups in terms of gender was not found. Conclusion As a result, increased number of relaxin receptors in the ligamentum teres could be a risk factor for DDH. Level of evidence Level 2, Prospective comparative study.

Differential Expression of the Androgen Receptor, Splice Variants and Relaxin 2 in Renal Cancer

Background: The role of the androgen receptor (AR) in renal cell carcinoma (RCC) is unclear. We aimed to analyze the expression of AR and its splice variants (SVs) and their correlation with relaxin 2 (RLN2) and cytokines in RCC. Methods: We investigated the expression of RLN2 and AR variants in 25 clear cell RCC (ccRCC) and 9 papillary (pRCC) tumor tissues and the corresponding controls using quantitative PCR and serum RLN2, testosterone and cytokine levels in matched samples using ELISA and chemiluminescent immunometric assay, respectively. Results: ccRCC tissues but not pRCC tissues more frequently expressed AR and the SVs than did normal tissues. All pRCC samples expressed more AR than did ccRCC samples. The highest expression of all AR variants except AR-V12 was found in low-stage tumors, with dominant expression of AR-V7. In males in the ccRCC cohort, the expression of AR-FL, AR-V1 and AR-V3 was significantly correlated with that of RLN2. The secretion pattern of proinflammatory IL-6 was higher in ccRCC than in pRCC. Conclusions: The results highlight additional molecular differences between ccRCC and pRCC, suggesting the influence of external factors on the whole kidney or genetic predispositions to developing certain types of renal cancer, and may support further pathological analysis and studies of targeted hormone therapy.

“Relaxin-dependent” way of implementing spontaneous preterm labor in multiple pregnancies: The involvement of placental relaxin 2

BACKGROUND: Despite numerous studies, the etiopathogenesis of preterm birth in multiple pregnancy remains unclear, which determines the low effectiveness of measures for the prevention of preterm birth. This fact makes it necessary to study possible ways of implementing preterm birth in multiple pregnancies and to search for new biomarkers of their pathogenetic links. Experimental and clinical studies have demonstrated the contribution of the pleiotropic hormone relaxin to the regulation of a wide range of physiological processes and its role in the implementation of the pathogenetic mechanisms of pregnancy complications, primarily premature birth. The proven autocrine / paracrine mechanism of placental relaxin action, which implements important local effects, determines the prospects for studying the contribution of its dysregulation to the implementation of spontaneous preterm labor in multiple pregnancies. MATERIALS AND METHODS: A morphological examination of 92 placentas from 46 deliveries of dichorionic diamniotic twins was performed: 24 of them were spontaneous premature births and 22 spontaneous term births. Histological examination of placentas along with immunohistochemical verification of relaxin 2 expression in the chorionic villus of the dichorial twins placentas were carried out. RESULTS: Histological examination of the dichorionic twins placentas revealed that those from spontaneous preterm birth were characterized by a higher frequency of chronic placental insufficiency with reduced compensatory and adaptive mechanisms and more pronounced circulatory disorders in the circulatory bed of the villous tree, when compared to placentas from spontaneous term labor. The first verification of relaxin 2 expression in the chorionic villi of the dichorionic twins placenta showed the role of the peptide in the initiation of spontaneous preterm birth. The relative area of relaxin 2 expression in spontaneous preterm labor was significantly higher (p 0.05) compared to that in spontaneous term labor. CONCLUSIONS: The data obtained confirm the hypothesis put forward about the involvement of placental relaxin in the pathogenesis of spontaneous preterm labor in multiple pregnancies. The authors were the first to propose the definition of a relaxin-dependent way of implementing spontaneous preterm labor. To help define new preventive strategies, the prospects for further studies of the role and significance of relaxin in the implementation of pathogenic processes involved in spontaneous preterm birth in multiple pregnancies have been outlined.

Are Hips Too Relaxed to Develop Healthy ?

Background: Developmental dysplasia of hip (DDH) etiology is still a controversial issue. While many factors involved in the etiology, one of which is the hormone relaxin. Relaxin concentrations in patients with DDH may lead to pathodynamic changes during hip development by altering the physiological nature of the ligament, as well as by long-term exposure to relaxin during pregnancy. Our objective in this study was to determine the quantity of relaxin receptors in the ligamentum teres and their part in causing DDH.Methods: We identified infants between birth and 3 years of age who had undergone open reduction for DDH between 2010 and 2012. 12 hips of 12 miss abortus fetus between 20 to 35 weeks of gestation were used as control group. Specimens obtained from two groups were stained with Relaxin-2 antibody and the amount of staining for relaxin receptors was determined using an ordinal H score. Results: The mean H scores of infants with DDH were significantly higher than those of controls (p=0.00). Conclusion: As a result, increased number of relaxin receptors in the ligamentum teres could be a risk factor for DDH and the number of relaxin receptors is an important clue in explaining the female:male ratio and clinical prognosis of early dysplastic hips.Level of Evidence: Level 2, Prospective comparative study

Quantity of Relaxin Receptors in the Ligament of Head of Femur in Infants with Developmental Hip Dysplasia

BackgroundDevelopmental dysplasia of hip (DDH) etiology is still a controversial issue. While many factors involved in the etiology, one of which is the hormone relaxin. Relaxin concentrations in patients with DDH may lead to pathodynamic changes during hip development by altering the physiological nature of the ligament, as well as by long-term exposure to relaxin during pregnancy. Our objective in this study was to determine the quantity of relaxin receptors in the ligamentum teres and their part in causing DDH.MethodsWe identified infants between birth and 3 years of age who had undergone open reduction for DDH between 2010 and 2012. 12 hips of 12 miss abortus fetus between 20 to 35 weeks of gestation were used as control group. Specimens obtained from two groups were stained with Relaxin-2 antibody and the amount of staining for relaxin receptors was determined using an ordinal H score. ResultsThe mean H scores of infants with DDH were significantly higher than those of controls (p=0.00). ConclusionAs a result, increased number of relaxin receptors in the ligamentum teres could be a risk factor for DDH and the number of relaxin receptors is an important clue in explaining the female:male ratio and clinical prognosis of early dysplastic hips.Level of Evidence: Level 2, Prospective comparative study

Human Recombinant Relaxin (Serelaxin) as Anti-fibrotic Agent: Pharmacology, Limitations and Actual Perspectives

: Relaxin (recombinant human relaxin-2 hormone; RLX-2; serelaxin) had raised expectations as a new medication for fibrotic diseases. A plethora of in vitro and in vivo studies have offered convincing demonstrations that relaxin promotes remodelling of connective tissue extracellular matrix mediated by inhibition of multiple fibrogenic pathways, especially the downstream signalling of transforming growth factor (TGF)-β1, a major pro-fibrotic cytokine, and the recruitment and activation of myofibroblast, the main fibrosis-generating cells. However, all clinical trials with relaxin in patients with fibrotic diseases gave inconclusive results. In this review, we have summarized the molecular mechanisms of fibrosis, highlighting those which can be effectively targeted by relaxin. Then, we have performed a critical reappraisal of the clinical trials performed to-date with relaxin as anti-fibrotic drug, in order to highlight their key points of strength and weakness and to identify some future opportunities for the therapeutic use of relaxin, or its analogues, in fibrotic diseases and pathologic scarring which, in our opinion, deserve to be investigated.

Relaxin 1 and Relaxin 2 are differentially expressed in the tumors of breast cancer patients treated with trastuzumab.

Trastuzumab (Herceptin) is a monoclonal antibody targeting the extracellular domain of the human epidermal growth factor receptor 2 (HER2) (1) utilized for the treatment of adjuvant and metastatic breast cancer (2) in the United States and worldwide. We mined published microarray data (3-5) to discover in an unbiased manner the most significant transcriptional changes associated with trastuzumab treatment. We identified both relaxin 1 and relaxin 2, encoded by RLN1 and RLN2 as among the genes most differentially expressed in the primary tumors and tumor cells of patients with breast cancer treated with trastuzumab. The primary tumors of breast cancer patients treated with trastuzumab expressed higher levels of RLN1 and RLN2 messenger RNA than did patients not treated with trastuzumab; a single administration of trastuzumab was sufficient to result in differential expression of RLN1 in primary tumors of the breast, demonstrating increased expression of a peptide hormone important in the central nervous system and for reproduction (6-8) as a transcriptional consequence of treatment with trastuzumab.

Relaxin-2 May Suppress Endometriosis by Reducing Fibrosis, Scar Formation, and Inflammation

Background: Relaxin (RLX)-2, produced by the corpus luteum and placenta, is known to be potentially effective in fibrotic diseases of the heart, lungs, kidneys, and bladder; however, its effectiveness in endometriosis has not yet been investigated. In the present study, we conducted a comprehensive study on the effect of RLX-2 on endometriosis. We checked the expressions of LGR-7, a primary receptor of RLX-2, in endometriomas using immunohistochemistry. Endometriotic stromal cells (ESCs) purified from surgical specimens were used in in vitro experiments. The effects of RLX-2 on ESCs were evaluated by quantitative-PCR, ELISA, and Western blotting. Gel contraction assay was used to assess the contraction suppressive effect of RLX-2. The effect of RLX-2 was also examined in the endometriosis mouse model. LGR-7 was expressed in endometriotic lesions. In ESCs, RLX-2 increased the production of cAMP and suppressed the secretion of interleukin-8, an inflammatory cytokine, by 15% and mRNA expression of fibrosis-related molecules, plasminogen activator inhibitor-1 (PAI-1), and collagen-I by approximately 50% (p < 0.05). In the gel contraction assay, RLX-2 significantly suppressed the contraction of ESCs, which was cancelled by removing RLX-2 from the medium or by adding H89, a Protein Kinase A (PKA) inhibitor. In ESCs stimulated with RLX-2, p38 MAPK phosphorylation was significantly suppressed. In the endometriosis mouse model, administration of RLX-2 significantly decreased the area of the endometriotic-like lesion with decreasing fibrotic component compared to non-treated control (p = 0.01). RLX-2 may contribute to the control of endometriotic lesion by suppressing fibrosis, scar formation, and inflammation.