Epigenetic remodeling by sex hormone receptors and implications for gender affirming hormone therapy.

Sex differences in immune system development and response to pathogens has been well documented, with females exhibiting more favorable outcomes for certain infections but a higher incidence of autoimmune disease compared to males. At least some of these sex differences are mediated by sex hormones, which signal through sex hormone receptors to remodel the regulatory chromatin landscape of cells. Here, we summarize the current knowledge of how sex hormone receptors remodel chromatin structure and epigenetic marks in different contexts in humans.

Mean Cartilage Attenuation Measured in an Osteoarthritis Mouse Model Using Contrast-Enhanced Micro-Computed Tomography is Indicative of Cartilage Degeneration.

ObjectiveTo develop and validate an image acquisition protocol for assessment of cartilage degeneration in an osteoarthritis (OA) mouse model using contrast-enhanced micro-computed tomography (CECT).DesignThree-, four-, seven-, and 10-month-old male STR/ort OA ( = 8) and healthy control CBA/1 ( = 8) mice were imaged using synchrotron-radiation micro-computed tomography. Mean attenuation of cartilage and mean attenuation difference between cartilage and contrast agent (mean Δ attenuation), to control for flux, were calculated and correlated to previously published cartilage parameters measured in the same mice.

High circulating concentrations of estradiol are anabolic for bone mass and strength in an adult male to female transgender mouse model.

The effects of gender affirming hormone therapy (GAHT) on bone microarchitecture and fracture risk in adult transgender women is unclear. To investigate the concept that skeletal integrity and strength in trans women may be improved by treatment with a higher dose of GAHT than commonly prescribed, we treated adult male mice with a sustained, high dose of estradiol. Adult male mice at 16 weeks of age were administered ~1.

Estradiol increases cortical and trabecular bone accrual and bone strength in an adolescent male-to-female mouse model of gender-affirming hormone therapy.

The effects of gender-affirming hormone therapy on the skeletal integrity and fracture risk in transitioning adolescent trans girls are unknown. To address this knowledge gap, we developed a mouse model to simulate male-to-female transition in human adolescents in whom puberty is first arrested by using gonadotrophin-releasing hormone analogs with subsequent estradiol treatment. Puberty was suppressed by orchidectomy in male mice at 5 weeks of age.

The Utility of Preclinical Models in Understanding the Bone Health of Transgender Individuals Undergoing Gender-Affirming Hormone Therapy.

Purpose Of Review: To summarise the evidence regarding the effects of gender-affirming hormone therapy (GAHT) on bone health in transgender people, to identify key knowledge gaps and how these gaps can be addressed using preclinical rodent models.

Recent Findings: Sex hormones play a critical role in bone physiology, yet there is a paucity of research regarding the effects of GAHT on bone microstructure and fracture risk in transgender individuals. The controlled clinical studies required to yield fracture data are unethical to conduct making clinically translatable preclinical research of the utmost importance.

A20 controls RANK-dependent osteoclast formation and bone physiology.

The anti-inflammatory protein A20 serves as a critical brake on NF-κB signaling and NF-κB-dependent inflammation. In humans, polymorphisms in or near the TNFAIP3/A20 gene have been associated with several inflammatory disorders, including rheumatoid arthritis (RA), and experimental studies in mice have demonstrated that myeloid-specific A20 deficiency causes the development of a severe polyarthritis resembling human RA. Myeloid A20 deficiency also promotes osteoclastogenesis in mice, suggesting a role for A20 in the regulation of osteoclast differentiation and bone formation.

The AR in bone marrow progenitor cells protects against short-term high-caloric diet-induced weight gain in male mice.

We previously identified a novel pathway of testosterone action via the androgen receptor (AR) in bone marrow mesenchymal precursor cells (BM-PCs) to negatively regulate fat mass and improve metabolic function in male mice. This was achieved using our PC-AR Gene Replacement mouse model in which the AR is only expressed in BM-PCs and deleted in all other tissues. We hypothesise that the markedly reduced fat mass and increased insulin sensitivity of PC-AR Gene Replacements will confer protection from diet-induced overweight and obesity.

The role of the androgen receptor in the pathogenesis of obesity and its utility as a target for obesity treatments.

Obesity is associated with hypothalamic-pituitary-testicular axis dysregulation in males. Here, we summarize recent evidence derived from clinical trials and studies in preclinical animal models regarding the role of androgen receptor (AR) signaling in the pathophysiology of males with obesity. We also discuss therapeutic strategies targeting the AR for the treatment of obesity and their limitations and provide insight into the future research necessary to advance this field.

Genetic Depletion of Amylin/Calcitonin Receptors Improves Memory and Learning in Transgenic Alzheimer's Disease Mouse Models.

Based upon its interactions with amyloid β peptide (Aβ), the amylin receptor, a class B G protein-coupled receptor (GPCR), is a potential modulator of Alzheimer's disease (AD) pathogenesis. However, past pharmacological approaches have failed to resolve whether activation or blockade of this receptor would have greater therapeutic benefit. To address this issue, we generated compound mice expressing a human amyloid precursor protein gene with familial AD mutations in combination with deficiency of amylin receptors produced by hemizygosity for the critical calcitonin receptor subunit of this heterodimeric GPCR.

Distinct roles of androgen receptor, estrogen receptor alpha, and BCL6 in the establishment of sex-biased DNA methylation in mouse liver.

Sexual dimorphism in gene regulation, including DNA methylation, is the main driver of sexual dimorphism in phenotypes. However, the questions of how and when sex shapes DNA methylation remain unresolved. Recently, using mice with different combinations of genetic and phenotypic sex, we identified sex-associated differentially methylated regions (sDMRs) that depended on the sex phenotype.

Changes in white adipose tissue gene expression in a randomized control trial of dieting obese men with lowered serum testosterone alone or in combination with testosterone treatment.

Purpose: The aim of this study was to determine early weight loss-associated changes in subcutaneous abdominal white adipose tissue (WAT) gene expression in obese men with lowered serum testosterone by RNA next-generation sequencing.

Methods: Fourteen men, mean age (IQR) 51.6 years (43.

Neuronal androgen receptor is required for activity dependent enhancement of peripheral nerve regeneration.

Neuronal activity after nerve injury can enhance axon regeneration and the restoration of function. The mechanism for this enhancement relies in part on hormone receptors, and we previously demonstrated that systemic androgen receptor antagonism blocked the effect of exercise or electrical stimulation on enhancing axon regeneration after nerve injury in both sexes. Here, we tested the hypothesis that the site of this androgen receptor signaling is both neuronal and involves the classical, genomic signaling pathway.

Vitamin D receptor expression in mature osteoclasts reduces bone loss due to low dietary calcium intake in male mice.

Mature osteoclasts express the vitamin D receptor (VDR) and are able to respond to active vitamin D (1α, 25-dihydroxyvitamin D; 1,25(OH)D) by regulating cell maturation and activity. However, the in vivo consequences of vitamin D signalling directly within functionally mature osteoclasts is only partially understood. To investigate the in vivo role of VDR in mature osteoclasts, conditional deletion of the VDR under control of the cathepsin K promoter (Ctsk/Vdr), was assessed in 6 and 12-week-old mice, either under normal dietary conditions (NormCaP) or when fed a low calcium (0.

The calcitonin receptor regulates osteocyte lacunae acidity during lactation in mice.

The physiological role of calcitonin, and its receptor, the CTR (or Calcr), has long been debated. We previously provided the first evidence for a physiological role of the CTR to limit maternal bone loss during lactation in mice by a direct action on osteocytes to inhibit osteocytic osteolysis. We now extend these findings to show that CTR gene expression is upregulated two- to three-fold in whole bone of control mice at the end of pregnancy (E18) and lactation (P21) compared to virgin controls.

Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia.

Atrial fibrillation, the most common cardiac arrhythmia, is an important contributor to mortality and morbidity, and particularly to the risk of stroke in humans. Atrial-tissue fibrosis is a central pathophysiological feature of atrial fibrillation that also hampers its treatment; the underlying molecular mechanisms are poorly understood and warrant investigation given the inadequacy of present therapies. Here we show that calcitonin, a hormone product of the thyroid gland involved in bone metabolism, is also produced by atrial cardiomyocytes in substantial quantities and acts as a paracrine signal that affects neighbouring collagen-producing fibroblasts to control their proliferation and secretion of extracellular matrix proteins.

Androgens stimulate erythropoiesis through the DNA-binding activity of the androgen receptor in non-hematopoietic cells.

Background: Androgens function through DNA and non-DNA binding-dependent signalling of the androgen receptor (AR). How androgens promote erythropoiesis is not fully understood.

Design And Methods: To identify the androgen signalling pathway, we treated male mice lacking the second zinc finger of the DNA-binding domain of the AR (AR ) with non-aromatizable 5α-dihydrotestosterone (5α-DHT) or aromatizable testosterone.

Sex-specific adipose tissue imprinting of regulatory T cells.

Adipose tissue is an energy store and a dynamic endocrine organ. In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism. Impaired VAT function-for example, in obesity-is associated with insulin resistance and type 2 diabetes.

The androgen receptor in the hypothalamus positively regulates hind-limb muscle mass and voluntary physical activity in adult male mice.

We have previously shown that expression of the androgen receptor (AR) in neurons within the brain positively regulates hind-limb muscle mass and physical activity in male mice. To further investigate the region of the brain responsible for mediating these effects of testosterone and to determine whether they are only important for muscle mass accrual during development or whether they are also important for the maintenance of muscle mass in the adult, we deleted the AR specifically in the hypothalamus of adult male mice (Hyp-ARKOs). Hyp-ARKO mice were generated by bilateral stereotaxic microinjection of an adeno-associated virus (AAV) expressing GFP and iCre recombinase under the control of the e-synapsin promoter into the hypothalamus of 10-week-old exon 3-AR floxed male mice.

The androgen receptor in bone marrow progenitor cells negatively regulates fat mass.

It is well established that testosterone negatively regulates fat mass in humans and mice; however, the mechanism by which testosterone exerts these effects is poorly understood. We and others have shown that deletion of the androgen receptor (AR) in male mice results in a phenotype that mimics the three key clinical aspects of hypogonadism in human males; increased fat mass and decreased bone and muscle mass. We now show that replacement of the gene specifically in mesenchymal progenitor cells (PCs) residing in the bone marrow of Global-ARKO mice, in the absence of the AR in all other tissues (PC-AR Gene Replacements), completely attenuates their increased fat accumulation.

Absence of vitamin D receptor in mature osteoclasts results in altered osteoclastic activity and bone loss.

Mature osteoclasts express the vitamin D receptor (VDR) and are able to synthesise and respond to 1,25(OH)D via CYP27B1 enzyme activity. Whether vitamin D signalling within osteoclasts is necessary for the regulation of osteoclastic bone resorption in an in vivo setting is unclear. To determine the requirement for the VDR- and CYP27B1-mediated activity in mature osteoclasts, conditional deletion mouse models were created whereby either Vdr or Cyp27b1 gene was inactivated by breeding either Vdr or Cyp27b1 mice with Cathepsin K-Cre transgenic mice (Cstk) to generate Ctsk/Vdr and Ctsk/Cyp27b1 mice respectively.