Publications by authors named "Rachel A Davey"

45 Publications

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

J Steroid Biochem Mol Biol 2021 Feb 26;210:105857. Epub 2021 Feb 26.

Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, SA, Australia. Electronic address:

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 (0.03 %), low phosphorous (0.08 %) diet (LowCaP). Splenocytes from Ctsk/Vdr mice were co-cultured with MLO-Y4 osteocyte-like cells to assess the effect on osteoclastogenesis. Six-week-old Ctsk/Vdr mice demonstrated a 10 % decrease in vertebral bone volume (p < 0.05), which was associated with increased osteoclast size (p < 0.05) when compared to Vdr control mice. Control mice fed a LowCaP diet exhibited extensive trabecular bone loss associated with increased osteoclast surface, number and size (p < 0.0001). Interestingly, Ctsk/Vdr mice fed a LowCaP diet showed exacerbated loss of bone volume fraction (BV/TV%) and trabecular number (Tb.N), by a further 22 % and 21 %, respectively (p < 0.05), suggesting increased osteoclastic bone resorption activity with the loss of VDR in mature osteoclasts under these conditions. Co-culture of Ctsk/Vdr splenocytes with MLO-Y4 cells increased resulting osteoclast numbers 2.5-fold, which were greater in nuclei density and exhibited increased resorption of dentine compared to osteoclasts derived from Vdr splenocyte cultures. These data suggest that in addition to RANKL-mediated osteoclastogenesis, intact VDR signalling is required for the direct regulation of the differentiation and activity of osteoclasts in both in vivo and ex vivo settings.
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http://dx.doi.org/10.1016/j.jsbmb.2021.105857DOI Listing
February 2021

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

J Endocrinol 2021 Feb 1. Epub 2021 Feb 1.

J Zajac, Department of Medicine (Austin Health), University of Melbourne, Heidelberg, 3084, Australia.

The physiological role of calcitonin, and its receptor, the CTR, 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 2-3 fold in whole bone of control mice at the end of pregnancy (E18) and lactation (P21) compared to virgin controls. This was associated with an increase in osteoclast activity evidenced by increases in osteoclast surface/bone surface and Dcstamp gene expression. To investigate the mechanism by which the CTR inhibits osteocytic osteolysis, in vivo acidification of the osteocyte lacunae during lactation (P14 days) was assessed using a pH indicator dye. A lower pH was observed in the osteocyte lacunae of lactating Global-CTRKOs compared to controls and was associated with an increase in the gene expression of ATPase H+ transporting V0 subunit D2 (Atp6v0d2) in whole bone of Global-CTRKOs at the end of lacation (P21). To determine whether the CTR is required for the replacement of mineral within the lacunae post-lactation, lacunar area was determined 3 weeks post-weaning. Comparison of the largest 20% of lacunae by area did not differ between Global-CTRKOs and controls post-lactation. These results provide evidence for CTR activation to inhibit osteocytic osteolysis during lactation being mediated by regulating the acidity of the lacunae microenvironment, whilst the CTR is dispensable for replacement of bone mineral within lacunae by osteocytes post-lactation.
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http://dx.doi.org/10.1530/JOE-20-0599DOI Listing
February 2021

Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia.

Nature 2020 11 4;587(7834):460-465. Epub 2020 Nov 4.

Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, John Radcliffe Hospital, Oxford, UK.

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. Global disruption of calcitonin receptor signalling in mice causes atrial fibrosis and increases susceptibility to atrial fibrillation. In mice in which liver kinase B1 is knocked down specifically in the atria, atrial-specific knockdown of calcitonin promotes atrial fibrosis and increases and prolongs spontaneous episodes of atrial fibrillation, whereas atrial-specific overexpression of calcitonin prevents both atrial fibrosis and fibrillation. Human patients with persistent atrial fibrillation show sixfold lower levels of myocardial calcitonin compared to control individuals with normal heart rhythm, with loss of calcitonin receptors in the fibroblast membrane. Although transcriptome analysis of human atrial fibroblasts reveals little change after exposure to calcitonin, proteomic analysis shows extensive alterations in extracellular matrix proteins and pathways related to fibrogenesis, infection and immune responses, and transcriptional regulation. Strategies to restore disrupted myocardial calcitonin signalling thus may offer therapeutic avenues for patients with atrial fibrillation.
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http://dx.doi.org/10.1038/s41586-020-2890-8DOI Listing
November 2020

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

Eur J Haematol 2020 Sep 15;105(3):247-254. Epub 2020 May 15.

Central Clinical School, Australian Centre for Blood Diseases, Monash University, Melbourne, Vic., Australia.

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. To distinguish direct hematopoietic and non-hematopoietic mechanisms, we performed bone marrow reconstitution experiments.

Results: In wild-type mice, 5α-DHT had greater erythroid activity than testosterone, which can be aromatized to estradiol. The erythroid response in wild-type mice following 5α-DHT treatment was associated with increased serum erythropoietin (EPO) and its downstream target erythroferrone, and hepcidin suppression. 5α-DHT had no erythroid activity in AR mice, proving the importance of DNA binding by the AR. Paradoxically, testosterone, but not 5α-DHT, suppressed EPO levels in AR mice, suggesting testosterone following aromatization may oppose the erythroid-stimulating effects of androgens. Female wild-type mice reconstituted with AR bone marrow cells remained responsive to 5α-DHT. In contrast, AR mice reconstituted with female wild-type bone marrow cells showed no response to 5α-DHT.

Conclusion: Erythroid promoting effects of androgens are mediated through DNA binding-dependent actions of the AR in non-hematopoietic cells, including stimulating EPO expression.
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http://dx.doi.org/10.1111/ejh.13431DOI Listing
September 2020

Sex-specific adipose tissue imprinting of regulatory T cells.

Nature 2020 03 26;579(7800):581-585. Epub 2020 Feb 26.

Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.

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. Regulatory T (T) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT. Here we uncover pronounced sexual dimorphism in T cells in the VAT. Male VAT was enriched for T cells compared with female VAT, and T cells from male VAT were markedly different from their female counterparts in phenotype, transcriptional landscape and chromatin accessibility. Heightened inflammation in the male VAT facilitated the recruitment of T cells via the CCL2-CCR2 axis. Androgen regulated the differentiation of a unique IL-33-producing stromal cell population specific to the male VAT, which paralleled the local expansion of T cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident T cells in a BLIMP1 transcription factor-dependent manner. Overall, we find that sex-specific differences in T cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation.
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http://dx.doi.org/10.1038/s41586-020-2040-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241647PMC
March 2020

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

J Steroid Biochem Mol Biol 2019 05 8;189:187-194. Epub 2019 Mar 8.

Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, 3084, Australia. Electronic address:

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. AR mRNA was deleted by 45% in the hypothalamus of Hyp-ARKOs at 5 weeks post-AAV-eSyn-iCre injection. This led to an increase in the mass of the androgen-dependent organs, seminal vesicles and kidneys, by 30% (P < 0.01) and 10% (P < 0.05) respectively, and an increase in serum luteinizing hormone (LH) by 2 fold (P < 0.05). Whilst the mean value for serum testosterone was higher in the Hyp-ARKOs, this did not reach statistical significance. Despite a phenotype consistent with increased androgen bioactivity in Hyp-ARKOs, which would be expected to increase muscle mass, the mass of the hind-limb muscles, gastrocnemius (Gast) (P = 0.001), extensor digitorum longus (EDL) (P < 0.001) and soleus (Sol) (P < 0.01) were paradoxically decreased by 12-19% compared to controls. Voluntary physical activity was reduced by 65% (P < 0.05) in Hyp-ARKO male mice and was associated with a reduction in gene expression of Drd1a and Maob (P ≤ 0.05) in the hypothalamus, suggesting involvement of the brain dopaminergic system. These data provide compelling evidence that androgen signalling via the AR in the hypothalamus acts to positively regulate the maintenance of hind-limb muscle mass and voluntary activity in adult male mice, independent of AR signalling in peripheral tissues.
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http://dx.doi.org/10.1016/j.jsbmb.2019.02.018DOI Listing
May 2019

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

J Endocrinol 2018 04 31;237(1):15-27. Epub 2018 Jan 31.

Department of MedicineAustin Health, University of Melbourne, Heidelberg, Victoria, Australia

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. Inguinal subcutaneous white adipose tissue and intra-abdominal retroperitoneal visceral adipose tissue depots in PC-AR Gene Replacement mice were 50-80% lower than wild-type (WT) and 75-90% lower than Global-ARKO controls at 12 weeks of age. The marked decrease in subcutaneous and visceral fat mass in PC-AR Gene Replacements was associated with an increase in the number of small adipocytes and a healthier metabolic profile compared to WT controls, characterised by normal serum leptin and elevated serum adiponectin levels. Euglycaemic/hyperinsulinaemic clamp studies reveal that the PC-AR Gene Replacement mice have improved whole-body insulin sensitivity with higher glucose infusion rates compared to WT mice and increased glucose uptake into subcutaneous and intra-abdominal fat. In conclusion, these data provide the first evidence for an action of androgens via the AR in mesenchymal bone marrow PCs to negatively regulate fat mass and improve metabolic function.
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http://dx.doi.org/10.1530/JOE-17-0656DOI Listing
April 2018

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

J Steroid Biochem Mol Biol 2018 03 28;177:77-82. Epub 2017 Oct 28.

School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5005, Australia. Electronic address:

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. To account for potential Ctsk-meaited off-target deletion of Vdr, Dmp1 were also used determine the effect of Vdr deletion in osteocytes. Furthermore, Ctsk/Vdr mice were ovariectomised (OVX) to assess the role of VDR in osteoclasts under bone-loss conditions and bone marrow precursor cells were cultured under osteoclastogenic conditions to assess osteoclast formation. Six-week-old Ctsk/Vdr female mice demonstrated a 15% decrease in femoral BV/TV (p<0.05). In contrast, BV/TV remained unchanged in Ctsk/Cyp27b1 mice as well as in Dmp1/VDR mice. When Ctsk/Vdr mice were subjected to OVX, the bone loss that occurred in Ctsk/Vdr was predominantly due to a diminished volume of thinner trabeculae when compared to control levels. These changes in bone volume in Ctsk/Vdr mice occurred without an observable histological change in osteoclast numbers or size. However, while cultured bone marrow-derived osteoclasts from Ctsk/Vdr mice were marginally increased when compared to VDR mice, elevated expression of genes such as Cathepsin K, Nfatc1 and VATPase was observed. Collectively, these data indicate that the absence of VDR in mature osteoclasts causes exacerbated bone loss in young mice and during OVX which is associated with enhanced osteoclastic activity and without increased osteoclastogenesis.
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http://dx.doi.org/10.1016/j.jsbmb.2017.10.022DOI Listing
March 2018

Androgen Action via the Androgen Receptor in Neurons Within the Brain Positively Regulates Muscle Mass in Male Mice.

Endocrinology 2017 10;158(10):3684-3695

Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria 3084, Australia.

Although it is well established that exogenous androgens have anabolic effects on skeletal muscle mass in humans and mice, data from muscle-specific androgen receptor (AR) knockout (ARKO) mice indicate that myocytic expression of the AR is dispensable for hind-limb muscle mass accrual in males. To identify possible indirect actions of androgens via the AR in neurons to regulate muscle, we generated neuron-ARKO mice in which the dominant DNA binding-dependent actions of the AR are deleted in neurons of the cortex, forebrain, hypothalamus, and olfactory bulb. Serum testosterone and luteinizing hormone levels were elevated twofold in neuron-ARKO males compared with wild-type littermates due to disruption of negative feedback to the hypothalamic-pituitary-gonadal axis. Despite this increase in serum testosterone levels, which was expected to increase muscle mass, the mass of the mixed-fiber gastrocnemius (Gast) and the fast-twitch fiber extensor digitorum longus hind-limb muscles was decreased by 10% in neuron-ARKOs at 12 weeks of age, whereas muscle strength and fatigue of the Gast were unaffected. The mass of the soleus muscle, however, which consists of a high proportion of slow-twitch fibers, was unaffected in neuron-ARKOs, demonstrating a stimulatory action of androgens via the AR in neurons to increase the mass of fast-twitch hind-limb muscles. Furthermore, neuron-ARKOs displayed reductions in voluntary and involuntary physical activity by up to 60%. These data provide evidence for a role of androgens via the AR in neurons to positively regulate fast-twitch hind-limb muscle mass and physical activity in male mice.
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http://dx.doi.org/10.1210/en.2017-00470DOI Listing
October 2017

Actin alpha cardiac muscle 1 gene expression is upregulated in the skeletal muscle of men undergoing androgen deprivation therapy for prostate cancer.

J Steroid Biochem Mol Biol 2017 11 27;174:56-64. Epub 2017 Jul 27.

Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia; Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia.

Androgen deprivation therapy (ADT) decreases muscle mass and function but no human studies have investigated the underlying genetic or cellular effects. We tested the hypothesis that ADT will lead to changes in skeletal muscle gene expression, which may explain the adverse muscle phenotype seen clinically. We conducted a prospective cohort study of 9 men with localised prostate cancer who underwent a vastus lateralis biopsy before and after 4 weeks of ADT. Next-generation RNA sequencing was performed and genes differentially expressed following ADT underwent gene ontology mining using Ingenuity Pathway Analysis. Differential expression of genes of interest was confirmed by quantitative PCR (Q-PCR) on gastrocnemius muscle of orchidectomised mice and sham controls (n=11/group). We found that in men, circulating total testosterone decreased from 16.5±4.3nmol/L at baseline to 0.4±0.15nmol/L post-ADT (p<0.001). RNA sequencing identified 19 differentially expressed genes post-ADT (all p<0.05 after adjusting for multiple testing). Gene ontology mining identified 8 genes to be of particular interest due to known roles in androgen-mediated signalling; ABCG1, ACTC1, ANKRD1, DMPK, THY1, DCLK1, CST3 were upregulated and SLC38A3 was downregulated post-ADT. Q-PCR in mouse gastrocnemius muscle confirmed that only one gene, Actc1 was concordantly upregulated (p<0.01) in orchidectomised mice compared with controls. In conclusion, given that ACTC1 upregulation is associated with improved muscle function in certain myopathies, we hypothesise that upregulation of ACTC1 may represent a compensatory response to ADT-induced muscle loss. Further studies will be required to evaluate the role and function of ACTC1.
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http://dx.doi.org/10.1016/j.jsbmb.2017.07.029DOI Listing
November 2017

Reduced bone formation markers, and altered trabecular and cortical bone mineral densities of non-paretic femurs observed in rats with ischemic stroke: A randomized controlled pilot study.

PLoS One 2017 9;12(3):e0172889. Epub 2017 Mar 9.

Stroke Division, The Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia.

Background: Immobility and neural damage likely contribute to accelerated bone loss after stroke, and subsequent heightened fracture risk in humans.

Objective: To investigate the skeletal effect of middle cerebral artery occlusion (MCAo) stroke in rats and examine its utility as a model of human post-stroke bone loss.

Methods: Twenty 15-week old spontaneously hypertensive male rats were randomized to MCAo or sham surgery controls. Primary outcome: group differences in trabecular bone volume fraction (BV/TV) measured by Micro-CT (10.5 micron istropic voxel size) at the ultra-distal femur of stroke affected left legs at day 28. Neurological impairments (stroke behavior and foot-faults) and physical activity (cage monitoring) were assessed at baseline, and days 1 and 27. Serum bone turnover markers (formation: N-terminal propeptide of type 1 procollagen, PINP; resorption: C-terminal telopeptide of type 1 collagen, CTX) were assessed at baseline, and days 7 and 27.

Results: No effect of stroke was observed on BV/TV or physical activity, but PINP decreased by -24.5% (IQR -34.1, -10.5, p = 0.046) at day 27. In controls, cortical bone volume (5.2%, IQR 3.2, 6.9) and total volume (6.4%, IQR 1.2, 7.6) were higher in right legs compared to left legs, but these side-to-side differences were not evident in stroke animals.

Conclusion: MCAo may negatively affect bone formation. Further investigation of limb use and physical activity patterns after MCAo is required to determine the utility of this current model as a representation of human post-stroke bone loss.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172889PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344372PMC
August 2017

Androgen Receptor Structure, Function and Biology: From Bench to Bedside.

Clin Biochem Rev 2016 Feb;37(1):3-15

Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, 3084, Australia.

The actions of androgens such as testosterone and dihydrotestosterone are mediated via the androgen receptor (AR), a ligand-dependent nuclear transcription factor and member of the steroid hormone nuclear receptor family. Given its widespread expression in many cells and tissues, the AR has a diverse range of biological actions including important roles in the development and maintenance of the reproductive, musculoskeletal, cardiovascular, immune, neural and haemopoietic systems. AR signalling may also be involved in the development of tumours in the prostate, bladder, liver, kidney and lung. Androgens can exert their actions via the AR in a DNA binding-dependent manner to regulate target gene transcription, or in a non-DNA binding-dependent manner to initiate rapid, cellular events such as the phosphorylation of 2(nd) messenger signalling cascades. More recently, ligand-independent actions of the AR have also been identified. Given the large volume of studies relating to androgens and the AR, this review is not intended as an extensive review of all studies investigating the AR, but rather as an overview of the structure, function, signalling pathways and biology of the AR as well as its important role in clinical medicine, with emphasis on recent developments in this field.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810760PMC
February 2016

Sex-related differences in the skeletal phenotype of aged vitamin D receptor global knockout mice.

J Steroid Biochem Mol Biol 2016 11 9;164:361-368. Epub 2015 Dec 9.

School of Pharmacy and Medical Sciences, Sansom Institute, University of South Australia, Adelaide, SA 5001, Australia; Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC, Australia; Centre for Orthopaedic and Trauma Research, School of Medicine, University of Adelaide, Adelaide, SA 5001, Australia.

The role of the vitamin D receptor (VDR) in maintaining skeletal health appears to be complex and dependent on the physiological context. Global Vdr deletion in a mouse model (Vdr) results in hypocalcemia, secondary hyperparathyroidism and bone features typical of vitamin D-dependent rickets type II. When weanling Vdr mice are fed a diet containing high levels of calcium, phosphorus and lactose, termed the rescue diet, normalisation of serum calcium, phosphate and parathyroid hormone levels results in prevention of rickets at 10 weeks of age. However, 17 week old male Vdr mice, fed the rescue diet, have been reported as osteopenic due to a decrease in bone formation when compared to wild type mice. We now report confirmation of this finding with further data on the effect of the rescue diet on appendicular and axial skeletal structures in male and female Vdr mice at 26 weeks of age compared to Vdr controls. All Vdr mice were normocalcemic with no evidence of any mineralization defect. However, male Vdr mice exhibited significantly reduced mineral in femoral and vertebral bones when compared to control littermate Vdr mice, consistent with the previously reported data. In contrast, 26-week-old female Vdr mice demonstrated significantly increased femoral trabecular bone volume although there was decreased vertebral trabecular bone volume, similar to males, and femoral cortical bone volume was unchanged. Thus, the Vdr mouse model displays sex- and site-specific differences in skeletal structures with long-term feeding of a rescue diet. Although the global Vdr ablation does not permit the determination of skeletal mechanisms producing these differences, these data confirm skeletal changes even when fed the rescue diet.
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http://dx.doi.org/10.1016/j.jsbmb.2015.12.005DOI Listing
November 2016

Wnt Signaling Inhibits Osteoclast Differentiation by Activating Canonical and Noncanonical cAMP/PKA Pathways.

J Bone Miner Res 2016 Jan 19;31(1):65-75. Epub 2015 Aug 19.

Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.

Although there has been extensive characterization of the Wnt signaling pathway in the osteoblast lineage, the effects of Wnt proteins on the osteoclast lineage are less well studied. We found that osteoclast lineage cells express canonical Wnt receptors. Wnt3a reduced osteoclast formation when applied to early bone-marrow macrophage (BMM) osteoclast differentiation cultures, whereas late addition did not suppress osteoclast formation. Early Wnt3a treatment inactivated the crucial transcription factor NFATc1 in osteoclast progenitors. Wnt3a led to the accumulation of nuclear β-catenin, confirming activation of canonical Wnt signaling. Reducing low-density lipoprotein receptor-related proteins (Lrp) 5 and Lrp6 protein expression prevented Wnt3a-induced inactivation of NFATc1; however, deletion of β-catenin did not block Wnt3a inactivation of NFATc1, suggesting that this effect was mediated by a noncanonical pathway. Wnt3a rapidly activated the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway and pharmacological stimulation of cAMP/PKA signaling suppressed osteoclast differentiation; Wnt3a-induced NFATc1 phosphorylation was blocked by inhibiting interactions between PKA and A-kinase anchoring proteins (AKAPs). These data indicate that Wnt3a directly suppresses osteoclast differentiation through both canonical (β-catenin) and noncanonical (cAMP/PKA) pathways in osteoclast precursors. In vivo reduction of Lrp5 and Lrp6 expressions in the early osteoclast lineage via Rank promoter Cre recombination reduced trabecular bone mass, whereas disruption of Lrp5/6 expression in late osteoclast precursors via cathepsin K (Ctsk) promoter Cre recombination did not alter the skeletal phenotype. Surprisingly, reduction of Lrp5/6 in the early osteoclast lineage decreased osteoclast numbers, as well as osteoblast numbers. Published studies have previously noted that β-catenin signaling is required for osteoclast progenitor proliferation. Our in vivo data suggest that Rank promoter Cre-mediated deletion of Lrp5/6 may similarly impair osteoclast progenitor proliferation.
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http://dx.doi.org/10.1002/jbmr.2599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758681PMC
January 2016

A Role for the Calcitonin Receptor to Limit Bone Loss During Lactation in Female Mice by Inhibiting Osteocytic Osteolysis.

Endocrinology 2015 Sep 2;156(9):3203-14. Epub 2015 Jul 2.

Department of Medicine (M.V.C., P.K.R., S.S., J.P.S., J.D.Z., R.A.D.), Austin Health, University of Melbourne, Heidelberg, 3084 Victoria, Australia; Centre for Orthopaedic and Trauma Research (D.M.F., G.J.A.), University of Adelaide, 5005 Adelaide, Australia; and School of Pharmacy and Medical Sciences (P.H.A.), University of South Australia, 5005 Adelaide, Australia.

During lactation, the large transfer of calcium from the mother to the milk is primarily sourced from the maternal skeleton. To determine whether the calcitonin receptor (CTR) plays a physiological role to protect the skeleton from excessive resorption during lactation, we assessed the maternal skeleton of global CTR knockout (CTRKO) and littermate control mice at the end of lactation (postnatal day 21). Micro-computed tomography analyses showed no effect on trabecular or cortical bone in the distal femur and L1 vertebra of maternal global CTR deletion at the end of lactation in global CTRKO mice compared with that in control mice. Bone resorption, as assessed by osteoclast number and activity at the end of lactation, was unaffected by maternal CTR deletion. Cathepsin K, carbonic anhydrase 2, matrix metalloproteinase 13, and receptor activator of nuclear factor-κB ligand mRNA levels, however, were markedly elevated by 3- to 6.5-fold in whole bone of lactating global CTRKO females. Because these genes have been shown to be up-regulated in osteocytes during lactation when osteocytes resorb their surrounding bone matrix, together with their reported expression of the CTR, we determined the osteocyte lacunar area in cortical bone. After lactation, the top 20% of osteocyte lacunar area in global CTRKO mice was 10% larger than the top 20% in control mice. These data are consistent with an increased osteocytic osteolysis in global CTRKO mice during lactation, which is further supported by the increased serum calcium observed in global CTRKO mice after lactation. These results provide evidence for a physiological role for the CTR to protect the maternal skeleton during lactation by a direct action on osteocytes to inhibit osteolysis.
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http://dx.doi.org/10.1210/en.2015-1345DOI Listing
September 2015

Osteoclast TGF-β Receptor Signaling Induces Wnt1 Secretion and Couples Bone Resorption to Bone Formation.

J Bone Miner Res 2016 Jan 6;31(1):76-85. Epub 2015 Aug 6.

Division of Endocrinology, Metabolism, Nutrition, and Diabetes, Mayo Clinic, Rochester, MN, USA.

Osteoblast-mediated bone formation is coupled to osteoclast-mediated bone resorption. These processes become uncoupled with age, leading to increased risk for debilitating fractures. Therefore, understanding how osteoblasts are recruited to sites of resorption is vital to treating age-related bone loss. Osteoclasts release and activate TGF-β from the bone matrix. Here we show that osteoclast-specific inhibition of TGF-β receptor signaling in mice results in osteopenia due to reduced osteoblast numbers with no significant impact on osteoclast numbers or activity. TGF-β induced osteoclast expression of Wnt1, a protein crucial to normal bone formation, and this response was blocked by impaired TGF-β receptor signaling. Osteoclasts in aged murine bones had lower TGF-β signaling and Wnt1 expression in vivo. Ex vivo stimulation of osteoclasts derived from young or old mouse bone marrow macrophages showed no difference in TGF-β-induced Wnt1 expression. However, young osteoclasts expressed reduced Wnt1 when cultured on aged mouse bone chips compared to young mouse bone chips, consistent with decreased skeletal TGF-β availability with age. Therefore, osteoclast responses to TGF-β are essential for coupling bone resorption to bone formation, and modulating this pathway may provide opportunities to treat age-related bone loss.
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http://dx.doi.org/10.1002/jbmr.2586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758668PMC
January 2016

The androgen receptor has no direct antiresorptive actions in mouse osteoclasts.

Mol Cell Endocrinol 2015 Aug 6;411:198-206. Epub 2015 May 6.

Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium. Electronic address:

Androgen deficiency or androgen receptor knockout (ARKO) causes high-turnover osteopenia, but the target cells for this effect remain unclear. To examine whether AR in osteoclasts directly suppresses bone resorption, we crossed AR-floxed with cathepsin K-Cre mice. Osteoclast-specific ARKO (ocl-ARKO) mice showed no changes neither in osteoclast surface nor in bone microarchitecture nor in the response to orchidectomy and androgen replacement, indicating that the AR in osteoclasts is not critical for bone maintenance. In line with the lack of a bone phenotype, the levels of AR were very low in osteoclast-enriched cultures derived from bone marrow (BM) and undetectable in osteoclasts generated from spleen precursors. Since tibiae of ubiquitous ARKO mice displayed increased osteoclast counts, the role of AR was further explored using cell cultures from these animals. Osteoclast generation and activity in vitro were similar between ARKO and wildtype control (WT) mice. In co-culture experiments, BM stromal cells (BMSCs) were essential for the suppressive action of AR on osteoclastogenesis and osteoclast activity. Stimulation with 1,25(OH)2 vitamin D3 increased Rankl and decreased Tnfsf11 (osteoprotegerin, Opg) gene expression in BMSCs more than in osteoblasts. This increase in the Rankl/Opg ratio following 1,25(OH)2D3 stimulation was lower, not higher, in ARKO mice. Runx2 expression in BMSCs was however higher in ARKO vs. WT, suggesting that ARKO mice may more readily commit osteoprogenitor cells to osteoblastogenesis. In conclusion, the AR does not seem to suppress bone resorption through direct actions in osteoclasts. BMSCs may however represent an alternative AR target in the BM milieu.
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http://dx.doi.org/10.1016/j.mce.2015.04.030DOI Listing
August 2015

Androgen receptor action in osteoblasts in male mice is dependent on their stage of maturation.

J Bone Miner Res 2015 May;30(5):809-23

Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Australia.

Androgen action via the androgen receptor (AR) is essential for normal skeletal growth and bone maintenance post-puberty in males; however, the molecular and cellular mechanisms by which androgens exert their actions in osteoblasts remains relatively unexplored in vivo. To identify autonomous AR actions in osteoblasts independent of AR signaling in other tissues, we compared the extent to which the bone phenotype of the Global-ARKO mouse was restored by replacing the AR in osteoblasts commencing at either the (1) proliferative or (2) mineralization stage of their maturation. In trabecular bone, androgens stimulated trabecular bone accrual during growth via the AR in proliferating osteoblasts and maintained trabecular bone post-puberty via the AR in mineralizing osteoblasts, with its predominant action being to inhibit bone resorption by decreasing the ratio of receptor activator of NF-κB ligand (RANKL) to osteoprotegerin (OPG) gene expression. During growth, replacement of the AR in proliferating but not mineralizing osteoblasts of Global-ARKOs was able to partially restore periosteal circumference, supporting the concept that androgen action in cortical bone to increase bone size during growth is mediated via the AR in proliferating osteoblasts. This study provides further significant insight into the mechanism of androgen action via the AR in osteoblasts, demonstrating that it is dependent on the stage of osteoblast maturation.
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http://dx.doi.org/10.1002/jbmr.2413DOI Listing
May 2015

Blunted sympathoinhibitory responses in obesity-related hypertension are due to aberrant central but not peripheral signalling mechanisms.

J Physiol 2014 Apr 3;592(7):1705-20. Epub 2014 Feb 3.

The gut hormone cholecystokinin (CCK) acts at subdiaphragmatic vagal afferents to induce renal and splanchnic sympathoinhibition and vasodilatation, via reflex inhibition of a subclass of cardiovascular-controlling neurons in the rostroventrolateral medulla (RVLM). These sympathoinhibitory and vasodilator responses are blunted in obese, hypertensive rats and our aim in the present study was to determine whether this is attributable to (i) altered sensitivity of presympathetic vasomotor RVLM neurons, and (ii) aberrant peripheral or central signalling mechanisms. Using a diet-induced obesity model, male Sprague-Dawley rats exhibited either an obesity-prone (OP) or obesity-resistant (OR) phenotype when placed on a medium high fat diet for 13-15 weeks; control animals were placed on a low fat diet. OP animals had elevated resting arterial pressure compared to OR/control animals (P < 0.05). Barosensitivity of RVLM neurons was significantly attenuated in OP animals (P < 0.05), suggesting altered baroreflex gain. CCK induced inhibitory responses in RVLM neurons of OR/control animals but not OP animals. Subdiaphragmatic vagal nerve responsiveness to CCK and CCK1 receptor mRNA expression in nodose ganglia did not differ between the groups, but CCK induced significantly less Fos-like immunoreactivity in both the nucleus of the solitary tract and the caudal ventrolateral medulla of OP animals compared to controls (P < 0.05). These results suggest that blunted sympathoinhibitory and vasodilator responses in obesity-related hypertension are due to alterations in RVLM neuronal responses, resulting from aberrant central but not peripheral signalling mechanisms. In obesity, blunted sympathoinhibitory mechanisms may lead to increased regional vascular resistance and contribute to the development of hypertension.
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http://dx.doi.org/10.1113/jphysiol.2013.269670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979620PMC
April 2014

Human androgen deficiency: insights gained from androgen receptor knockout mouse models.

Asian J Androl 2014 Mar-Apr;16(2):169-77

Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.

The mechanism of androgen action is complex. Recently, significant advances have been made into our understanding of how androgens act via the androgen receptor (AR) through the use of genetically modified mouse models. A number of global and tissue-specific AR knockout (ARKO) models have been generated using the Cre-loxP system which allows tissue- and/or cell-specific deletion. These ARKO models have examined a number of sites of androgen action including the cardiovascular system, the immune and hemopoetic system, bone, muscle, adipose tissue, the prostate and the brain. This review focuses on the insights that have been gained into human androgen deficiency through the use of ARKO mouse models at each of these sites of action, and highlights the strengths and limitations of these Cre-loxP mouse models that should be considered to ensure accurate interpretation of the phenotype.
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http://dx.doi.org/10.4103/1008-682X.122590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955325PMC
November 2014

Normal phenotype in conditional androgen receptor (AR) exon 3-floxed neomycin-negative male mice.

Endocr Res 2014 27;39(3):130-5. Epub 2014 Jan 27.

Department of Medicine, Austin Health, University of Melbourne , Heidelberg, VIC , Australia.

Androgens (testosterone and dihydrotestosterone) acting via the androgen receptor (AR) are required for male sexual differentiation, and also regulate the development of many other tissues including muscle, fat and bone. We previously generated an AR(lox) mouse line with exon 3 of the AR gene targeted by loxP sites. The deletion of exon 3 is in-frame, so only the DNA binding-dependent actions of the AR are deleted, but non-DNA binding-dependent actions are retained. This line also contained an antibiotic resistance selection cassette, neomycin (neo) in intron 3, which was also flanked by loxP sites. Hemizygous AR(lox) male mice demonstrated a phenotype of hyperandrogenization, with increased mass of androgen-dependent tissues. We hypothesized that this hyperandrogenization was likely to be due to the presence of the neo cassette. In this study, we have generated an AR(lox) neo-negative mouse line, using the EIIa-cre deleter mouse line to remove the neo cassette. Hemizygous AR(lox) neo-negative male mice have a normal phenotype, with normal body mass and normal mass of androgen-dependent tissues including the testis, seminal vesicles, kidney, spleen, heart and retroperitoneal fat. This neo-negative exon 3-targeted mouse line is the only floxed AR mouse line available to study the DNA binding-dependent actions of the AR in a tissue-specific manner, and is suitable for investigation in all tissues. This study demonstrates the importance of removing the selection cassette, which can potentially alter the phenotype of floxed mouse lines even in the absence of detectable effects on target gene expression.
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http://dx.doi.org/10.3109/07435800.2013.864303DOI Listing
January 2015

Calcitonin: physiology or fantasy?

J Bone Miner Res 2013 May;28(5):973-9

Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.

Calcitonin, a potent hypocalcemic hormone produced by the C-cells of the thyroid, was first discovered by Harold Copp in 1962. The physiological significance of calcitonin has been questioned, but recent studies using genetically modified mouse models have uncovered additional actions of calcitonin acting through its receptor (CTR) that are of particular significance to the regulation of bone and calcium homeostasis. Mice in which the CTR is deleted in osteoclasts are more susceptible to induced hypercalcemia and exogenous calcitonin is able to lower serum calcium in younger animals. These data are consistent with the hypothesis that calcitonin can regulate serum calcium by inhibiting the efflux of calcium from bone, and that this action is most important when bone turnover is high. Calcitonin has also been implicated in protecting the skeleton from excessive loss of bone mineral during times of high calcium demand, such as lactation. This action may be linked to an intriguing and as yet unexplained observation that calcitonin inhibits bone formation, because deletion of the CTR leads to increased bone formation. We propose several mechanisms by which calcitonin could protect the skeleton by regulating bone turnover, acting within the bone and/or centrally. A new more holistic notion of the physiological role of calcitonin in bone and calcium homeostasis is required and we have highlighted some important knowledge gaps so that future calcitonin research will help to achieve such an understanding.
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http://dx.doi.org/10.1002/jbmr.1869DOI Listing
May 2013

The pleiotropic effects of vitamin D in bone.

J Steroid Biochem Mol Biol 2013 Jul 5;136:190-4. Epub 2012 Sep 5.

School of Pharmacy and Medical Sciences, University of South Australia, Adelaide 5000, Australia.

A current controversial question related to vitamin D supplementation is what level of serum 25-hydroxyvitamin D3 (25(OH)D3) is required to reduce the incidence of osteoporotic fractures. The reasoning behind vitamin D supplementation has been mostly derived from the role of vitamin D to promote intestinal calcium absorption and reduce bone resorption. While minimum 25(OH)D3 levels of 20nmol/L are required for sufficient intestinal calcium absorption to prevent osteomalacia, the mechanistic details of how higher 25(OH)D3 levels, well beyond that required for optimal calcium absorption, are able to prevent fractures and increase bone mineral density is unclear. Substantial evidence has arisen over the past decade that conversion of 25(OH)D3 to 1,25(OH)2D3via the 1-alpha hydroxylase (CYP27B1) enzyme in osteoblasts, osteocytes, chondrocytes and osteoclasts regulates processes such as cell proliferation, maturation and mineralization as well as bone resorption, which are all dependent on the presence the of the vitamin D receptor (VDR). We and others have also shown that increased vitamin D activity in mature osteoblasts by increasing levels of VDR or CYP27B1 leads to improved bone mineral volume using two separate transgenic mouse models. While questions remain regarding activities of vitamin D in bone to influence the anabolic and catabolic processes, the biological importance of vitamin D activity within the bone is unquestioned. However, a clearer understanding of the varied mechanisms by which vitamin D directly and indirectly influences mineral bone status are required to support evidence-based recommendations for vitamin D supplementation to reduce the risk of fractures. This article is part of a Special Issue entitled 'Vitamin D workshop'.
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http://dx.doi.org/10.1016/j.jsbmb.2012.08.008DOI Listing
July 2013

Identification of gene pathways altered by deletion of the androgen receptor specifically in mineralizing osteoblasts and osteocytes in mice.

J Mol Endocrinol 2012 Aug 29;49(1):1-10. Epub 2012 May 29.

Department of Medicine, Austin Health, University of Melbourne, Studley Road, Heidelberg, Victoria 3084, Australia.

Androgens play a key role in skeletal growth and maintenance in males and can mediate their actions, at least in part, via the androgen receptor (AR) in osteoblasts. To investigate the mechanisms by which androgens exert their effects via the AR in mineralizing osteoblasts and osteocytes, we identified gene targets/pathways regulated by the AR using targeted gene expression and microarray approaches on bone isolated from mice in which the AR is specifically deleted in mineralizing osteoblasts and osteocytes (mOBL-ARKOs). Gene ontology mining indicated a number of biological processes to be affected in the bones of mOBL-ARKOs including skeletal and muscular system development and carbohydrate metabolism. All genes identified to have altered expression in the bones of mOBL-ARKOs were confirmed by Q-PCR for their androgen responsiveness in an androgen deprivation and replacement mouse model. The osteoblast genes Col1a1 and Bglap and the osteoclast genes Ctsk and RANKL (Tnfs11) were upregulated in the bones of mOBL-ARKOs, consistent with the increased matrix synthesis, mineralization, and bone resorption observed previously in these mice. Of significant interest, we identified genes involved in carbohydrate metabolism (adiponectin and Dpp4) and in growth and development (GH, Tgfb (Tgfb2), Wnt4) as potential targets of androgen action via the AR in mineralizing osteoblasts.
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http://dx.doi.org/10.1530/JME-12-0014DOI Listing
August 2012

Decreased body weight in young Osterix-Cre transgenic mice results in delayed cortical bone expansion and accrual.

Transgenic Res 2012 Aug 13;21(4):885-93. Epub 2011 Dec 13.

Department of Medicine, Austin Health, University of Melbourne, Studley Road, Heidelberg, VIC 3084, Australia.

Conditional gene inactivation using the Cre/loxP system has lead to significant advances in our understanding of the function of genes in a wide range of disciplines. It is becoming increasingly apparent in the literature, that Cre transgenic mice may themselves have a phenotype. In the following study we describe the bone phenotype of a commonly used Cre transgenic mouse line to study osteoblasts, the Osx-GFP::Cre (Osx-Cre) mice. Cortical and trabecular bone parameters were determined in the femurs of Osx-Cre mice at 6 and 12 weeks of age by microtomography (μCT). At 6 weeks of age, Osx-Cre mice had reduced body weight by 22% (P < 0.0001) and delayed cortical bone expansion and accrual, characterized by decreases in periosteal circumference by 7% (P < 0.05) and cortical thickness by 11% (P < 0.01), compared to wild type controls. Importantly, the cortical bone phenotype of the skeletally immature Osx-Cre mice at 6 weeks of age could be accounted for by their low body weight. The delayed weight gain and cortical growth of Osx-Cre mice was overcome by 12 weeks of age, with no differences observed between Osx-Cre and wild type controls. In conclusion, Osx-Cre expressing mice display a delayed growth phenotype in the absence of doxycycline treatment, evidenced by decreased cortical bone expansion and accrual at 6 weeks of age, as an indirect result of decreased body weight. While this delay in growth is overcome by adulthood at 12 weeks of age, caution together with appropriate data analysis must be considered when assessing the experimental data from skeletally immature Cre/loxP knockout mice generated using the Osx-Cre mouse line to avoid misinterpretation.
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http://dx.doi.org/10.1007/s11248-011-9581-zDOI Listing
August 2012

A physiological role for androgen actions in the absence of androgen receptor DNA binding activity.

Mol Cell Endocrinol 2012 Jan 22;348(1):189-97. Epub 2011 Aug 22.

Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Vic. 3084, Australia.

We tested the hypothesis that androgens have physiological actions via non-DNA binding-dependent androgen receptor (AR) signaling pathways in males, using our genetically modified mice that express a mutant AR with deletion of the 2nd zinc finger of the DNA binding domain (AR(ΔZF2)) that cannot bind DNA. In cultured genital skin fibroblasts, the mutant AR(ΔZF2) has normal ligand binding ability, phosphorylates ERK-1/2 in response to 1 min DHT treatment (blocked by the AR antagonist bicalutamide), but has reduced androgen-dependent nuclear localization compared to wildtype (WT). AR(ΔZF2) males have normal baseline ERK-1/2 phosphorylation, with a 1.5-fold increase in Akt phosphorylation in AR(ΔZF2) muscle vs WT. To identify physiological actions of non-DNA binding-dependent AR signaling, AR(ΔZF2) males were treated for 6 weeks with dihydrotestosterone (DHT). Cortical bone growth was suppressed by DHT in AR(ΔZF2) mice (6% decrease in periosteal and 7% decrease in medullary circumference vs untreated AR(ΔZF2) males). In conclusion, these data suggest that non-DNA binding dependent AR actions suppress cortical bone growth, which may provide a mechanism to fine-tune the response to androgens in bone.
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http://dx.doi.org/10.1016/j.mce.2011.08.017DOI Listing
January 2012

The role of the calcitonin receptor in protecting against induced hypercalcemia is mediated via its actions in osteoclasts to inhibit bone resorption.

Bone 2011 Feb 17;48(2):354-61. Epub 2010 Sep 17.

Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.

Despite the therapeutic value of calcitonin in treating bone disease, a biological role of endogenous calcitonin is controversial. Having previously demonstrated that the CTR has a biological role in protecting against calcium stress using a global CTRKO mouse model, the purpose of this study was to determine whether the protection conferred by the CTR during induced hypercalcemia is mediated via CTR expression on osteoclasts. Mice were generated, in which the CTR was deleted specifically within osteoclasts (OCL-CTRKOs) and compared with mice in which the CTR was deleted globally (global CTRKOs). Significantly, peak serum calcium levels following induced hypercalcemia were >18% higher in global-CTRKOs and OCL-CTRKOs than controls (P<0.01) due to increased bone resorption (P<0.05). Peak serum calcium levels relative to controls were greater in global-CTRKO males than OCL-CTRKO males (P<0.001), which may, at least in part, be due to increased reabsorption of calcium in the kidney (P<0.01). Controls for all analyses were sex-matched littermates with normal CTR expression. In conclusion, the CTR protects against hypercalcemia predominantly via its inhibitory action on osteoclasts.
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http://dx.doi.org/10.1016/j.bone.2010.09.013DOI Listing
February 2011

DNA-binding-dependent androgen receptor signaling contributes to gender differences and has physiological actions in males and females.

J Endocrinol 2010 Jul 15;206(1):93-103. Epub 2010 Apr 15.

Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.

We used our genomic androgen receptor (AR) knockout (ARKO) mouse model, in which the AR is unable to bind DNA to: 1) document gender differences between males and females; 2) identify the genomic (DNA-binding-dependent) AR-mediated actions in males; 3) determine the contribution of genomic AR-mediated actions to these gender differences; and 4) identify physiological genomic AR-mediated actions in females. At 9 weeks of age, control males had higher body, heart and kidney mass, lower spleen mass, and longer and larger bones compared to control females. Compared to control males, ARKO males had lower body and kidney mass, higher splenic mass, and reductions in cortical and trabecular bone. Deletion of the AR in ARKO males abolished the gender differences in heart and cortical bone. Compared with control females, ARKO females had normal body weight, but 14% lower heart mass and heart weight/body weight ratio. Relative kidney mass was also reduced, and relative spleen mass was increased. ARKO females had a significant reduction in cortical bone growth and changes in trabecular architecture, although with no net change in trabecular bone volume. In conclusion, we have shown that androgens acting via the genomic AR signaling pathway mediate, at least in part, the gender differences in body mass, heart, kidney, spleen, and bone, and play a physiological role in the regulation of cardiac, kidney and splenic size, cortical bone growth, and trabecular bone architecture in females.
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http://dx.doi.org/10.1677/JOE-10-0026DOI Listing
July 2010