Relaxin to augment height?

Relaxin may play a role in the observed height increase and foot size increase in some pregnances.  Relaxin may be used as a novel way of weakening the type I collagen in the bone enabling the bone to be less resistant to stretch.

Pelvic development as affected by relaxin in three genetically selected frame sizes of beef heifers.

"Purified porcine relaxin was administered into the cervical os on Day 278 of gestation to determine its effects on pelvic development in three genetically selected frame sizes of primiparous beef heifers. Heifers were categorized as small, medium and large frame based upon their genetic composition. Pelvic height, pelvic width and cervical dilatation were determined from Day 270 to 2 days postpartum. On Day 270, heifers were assigned at random to one of three treatments: vehicle control, n = 16; relaxin once (3,000 U), n = 14; and relaxin twice (2 times 3,000 U 12 h apart), n = 17. Each heifer-frame size was represented in each treatment. Relaxin caused marked increases in pelvic height and width, as well as in the rate of linear increase (cm/day) of these parameters (p less than 0.05). These linear increases in pelvic height were 510, 264 and 204%, and pelvic width, were 280, 213 and 204% of the respective pretreatment rates for small, medium and large heifers. The rate of linear increase in pelvic width was greater than pelvic height in all heifers, but maximal in small-frame heifers; relaxin attenuated these intrinsic differences. For small heifers, the rate of linear increase in pelvic width was 121 and 145% of increases for medium and large heifers, respectively, before treatment, and 160 and 200% after treatment. The rate of postpartum involution of pelvic width was -0.03, -0.36 and -0.50 cm/day and, for pelvic height, -0.02, -0.27 and -0.29 cm/day in small, medium and large heifers, respectively."

"pelvic area in beef heifers increases normally from 200 to 250 cm^2."

"During gestation, the pelvis grows linearly at about 0.5 cm^2 /day."

"All heifers were bred by artificial insemination at estrus (Day 0); pregnancy lasts approximately 283 days. Heifers calved at an average age of 25 ± 1 mo (± SE)."

Relaxin was injected directly into the cervix.

Relaxin increases human endothelial progenitor cell NO and migration and vasculogenesis in mice.

"The ovarian peptide hormone, relaxin, circulates during pregnancy, contributing to profound maternal vasodilation through endothelial and nitric oxide (NO)-dependent mechanisms. Circulating numbers of bone marrow-derived endothelial cells (BMDECs), which facilitate angiogenesis and contribute to repair of vascular endothelium, increase during pregnancy. Relaxin enhances BMDEC NO production, circulating numbers, and function. Recombinant human relaxin-2 (rhRLX) stimulated PI3K/Akt B-dependent NO production in human BMDECs within minutes, and activated BMDEC migration that was inhibited by L-N(G)-nitroarginine methyl ester. In BMDECs isolated from relaxin/insulin-like family peptide receptor 2 gene (Rxfp2) knockout and wild-type mice, but not Rxfp1 knockout mice, rhRLX rapidly increased NO production. Similarly, rhRLX increased circulating BMDEC number in Rxfp2 knockout and wild-type mice, but not Rxfp1 knockout mice as assessed by colony formation and flow cytometry. Relaxin effects BMDEC function through the RXFP1 receptor. Both vascularization and incorporation of GFP-labeled BMDECs were stimulated in rhRLX-impregnated Matrigel pellets implanted in mice. Relaxin is a regulator of BMDECs number and function, which has implications for angiogenesis and vascular remodeling."

"cause morphologic changes in endothelial cells of endometrial blood vessels consistent with hypertrophy and hyperplasia, and enlargement of arterioles and capillaries"<-maybe Relaxin can cause hypertrophy and hyperplasia in bones and chondrocytes too.

"Humans have 3 relaxin genes, designated relaxin-1, -2, and -3. Rats and mice each have 2 relaxin genes designated relaxin-1 and -3. Human relaxin-2, as well as rat and mouse relaxin-1 gene products, are true orthologs, insofar as they are secreted by the corpus luteum during pregnancy and circulate. Humans, rats, and mice have 1 relaxin receptor, the LGR7 (leucine rich repeat-containing G protein coupled) receptor recently renamed relaxin/insulin-like family peptide 1 receptor, RXFP1. Although human relaxin may also bind to the LGR8 receptor (RXFP2), albeit with reduced affinity, the preferred ligand for RXFP2 is insulin-like 3 (INSL3). Recently, 2 new receptors have been described for relaxin-3, GPCR135 and 142, although GPCR142 is a pseudogene in rats."

Relaxin stimulates osteoclast differentiation and activation. states that Relaxin induces osteoclast differentiation.

Relaxin affects the dentofacial sutural tissues.

"Relaxin might modulate the remodeling of connective tissue within the craniofacial sutures and periodontal tissues. Relaxin is produced by the pregnant female. It is responsible for the relaxing of the pubic symphysis; the birth canal is widened for parturition. It has also [has] effects on other areas of the body, including ligaments and regions containing collagen and fibroblastic activity. Twenty-one Swiss retired-breeder mice were used to: 1) demonstrate the presence of relaxin within the sutures; 2) demonstrate its effects on the integrity of the suture-like tissues; and 3) assay its effects on protease activity. Relaxin in concentrations of 250 and 500 ng/ml was used in the treated samples and allowed to incubate in complete tissue culture for 24 h. Relaxin [is present] within the cranial suture. [There were] definite changes in the collagen fibril arrangement in the PDL[periodontal ligament] - from being dense and highly organized with a perpendicular direction between tooth and bone to randomly organized and loose, lacking any direction between tooth and bone. An elevation in the protease activity was evident in the relaxin-treated samples."

"In the pregnant female, [relaxin] interferes with the collagen types I and III gene expression, reduces total collagen, and increases the collagenase activity."

"Relaxin has also been found to be produced in the male, the primary source being the prostate gland, though it has not been possible to demonstrate its release into the peripheral blood"

"Relaxin-treated samples had collagen fibrils that were disorganized and dispersed.  The cervices became soft and more extensible."<-so maybe relaxin allows for bone stretching.

"relaxin was shown to inhibit collagen accumulation in a dose-dependent manner"

Effect of relaxin on the phenotype of collagens synthesized by cultured rabbit chondrocytes.

"The effect of porcine relaxin on rabbit articular and growth plate chondrocytes in primary culture was investigated by measurement of total collagen production and analysis of the phenotypes of newly synthesized collagen chains. A 24-h treatment of monolayer articular and multilayer growth plate chondrocytes with 2 micrograms per ml relaxin had no effect on total DNA and did not significantly modify the amount of [3H]proline-labelled collagen chains secreted by the cells. However, polyacrylamide gel electrophoresis demonstrated relevant modifications in relaxin treated chondrocytes. A significant increase was observed in the proportion of type III collagen and in the intensity of the band corresponding to alpha 2I chains. Two-dimensional peptide mapping of CNBr-cleaved molecules indicated that the band that was identified as alpha 1II on monodimensional gels contained a significant proportion of alpha 1I collagen chains, as demonstrated by the presence of alpha 1I cyanogen bromide-digested peptides. The intensity of this band was increased by relaxin treatment. Furthermore, total RNA analysis by slot blot and Northern blot techniques showed a dose-dependent stimulation of alpha 1I and alpha 1III mRNA levels after incubation with increased relaxin concentrations, but no change in the amount of alpha 1II mRNA. These results suggested that when added to cartilage cells in vitro, relaxin modulated the expression of type I, type II and type III collagen genes by amplifying the dedifferentiation process."

So you don't want relaxin with active growth plates but maybe with closed growth plates relaxin causes dedifferentiation of osteoblasts and bone collagen allowing for stretching and formation of new growth plates.

"relaxin acts on the pubic symphisis before and during parturition by softening and lengthening the pubic cartilage and the interpubic ligament"

Effect of pregnancy and obesity on arch of foot.

"Endocrine changes[like relaxin] occurring during pregnancy result in increased laxity of the ligaments of the foot. This may lead to gradual collapse of the foot arches. [We] determine whether pregnancy and body mass index (BMI) had a role in affecting the foot arches at long term.

A collapsed arch results in widening of the feet, thus altering the foot size. The control group included nulliparous women, while the study group included women who had been pregnant at least once. The groups were stratified secondarily by obesity according to BMI. We reviewed over 1000 charts. The age, BMI, and shoe size in an athletic shoe were recorded.

There were 40 subjects in the control group and 70 in the study group. 19/40 women in control and 46/70 in study group experienced a change in shoe size (P = 0.06). Of those affected, the non-obese control group experienced a 9.7% change in shoe size while the obese study group experienced a 15.5% change.

There was neither a change in size between women who had been pregnant and the nulliparous, nor was there a difference between the obese and non-obese. However, there was a statically significant difference between those affected who were both non-obese and nulliparous and those who had been pregnant and who are obese. Individually, the effect of pregnancy and BMI are highly suggestive and clinically relevant."

[Changes in shape and size of the foot during pregnancy].

"Many women report an increase in foot size during their pregnancy. In an initial survey of 21 mothers in 2 Münster nursery schools we found a tendency towards an increase in foot size during pregnancy. We  measure changes in foot length, width, height and volume. A total of 40 women recruited from the antenatal clinic of the University Hospital of Münster and a participating practice were seen three times during their pregnancy. We found a statistically significant increase in foot length, width and volume, whereas foot height decreased slightly. This difference was, however, not significant."

"the overall contact surface of the foot in pregnant women was greater by 12% than in the control group."<-maybe due to collapsed arches?

"a consequence of an altered weight bearing (half a body weight to the body weight), the extension of the foot by 0.7%, the widening of the forefoot by 3.1% and the broadening of the hindfoot by 2.8%, with the width of the rear foot increased by 8.7% compared to the unloaded condition and the forefoot by 6%. The average weight gain of a woman at the end of pregnancy is about 12 kg, which are distributed more or less equally to an increase in fat deposits and water retention"

"Changes in foot size may be due to fluid retention during pregnancy. Occurring edema of the ankles and legs are partly due to the compression of the venous system through the uterus"<-like hydrostatic pressure via LSJL.

Relaxin induces matrix-metalloproteinases-9 and -13 via RXFP1: induction of MMP-9 involves the PI3K, ERK, Akt and PKC-ζ pathways.

"Relaxin treatment of cells in which RXFP1 was silenced resulted in diminished induction of MMP-9 and -13 by relaxin, whereas overexpression of RXFP1 potentiated the relaxin-induced expression of these proteinases. Suppression or overexpression of RXFP2 resulted in no changes in the relaxin-induced MMP-9 and -13. Studies using chemical inhibitors and siRNAs to signaling molecules showed that PI3K, Akt, ERK and PKC-ζ and the transcription factors Elk-1, c-fos and, to a lesser extent, NF-κB are involved in relaxin's induction of MMP-9."

"The human relaxin H2 activates both RXFP1 and RXFP2 resulting in an increase in intracellular cAMP concentrations"

"relaxin H2 induces MMP-9 and -13 in fibrochondrocytes through the RXFP1 receptor, and that relaxin’s modulation of MMP-9 occurs via PI3K–AKT–PKCζ–ERK1/2 signaling pathway and involves Elk-1 and c-fos transcription factors."

"In addition to activating ERK1/2, PI3K and Akt, relaxin treatment also enhances phosphorylation of PKC and PKC-ζ [which can prevent the degradation of NFKb by IKb"