Biomedical subjects

Rachel A Davey

Publications and source records attributed to Rachel A Davey.

8 recordsLinked to original sources

PubMed2007

Osteoblast deletion of exon 3 of the androgen receptor gene results in trabecular bone loss in adult male mice.

UNLABELLED: The mechanism of androgen action on bone was studied in male mice with the AR deleted in mature osteoblasts. These mice had decreased trabecular bone volume associated with a decrease in trabecular number, suggesting that androgens may act directly on osteoblasts to maintain trabecular bone. INTRODUCTION: Androgens modulate bone cell activity and are important for the maintenance of bone mass. However, the mechanisms by which they exert these actions on bone remain poorly defined. The aim of this study was to investigate the role of androgens acting through the classical androgen receptor (AR) signaling pathways (i.e., DNA-binding dependent pathways) in osteoblasts using male mice in which exon 3 of the AR gene was deleted specifically in mature osteoblasts. MATERIALS AND METHODS: Mice with a floxed exon 3 of the AR gene were bred with Col 2.3-cre transgenic mice, in which Cre recombinase is expressed in mineralizing osteoblasts. The skeletal phenotype of mutant mice was assessed by histomorphometry and quantitative microCT at 6, 12, and 32 weeks of age (n=8 per group). Wildtype, hemizygous exon 3 floxed and hemizygous Col 2.3-cre male littermates were used as controls. Data were analyzed by one-way ANOVA and Tukey's posthoc test. RESULTS: microCT analysis of the fifth lumbar vertebral body showed that these mice had reduced trabecular bone volume (p<0.05) at 32 weeks of age compared with controls. This was associated with a decrease in trabecular number (p<0.01) at 12 and 32 weeks of age, suggesting increased bone resorption. These effects were accompanied by a reduction in connectivity density (p<0.01) and an increase in trabecular separation (p<0.01). A similar pattern of trabecular bone loss was observed in the distal femoral metaphysis at 32 weeks of age. CONCLUSIONS: These findings show that inactivation of the DNA binding-dependent functions of the AR, specifically in mature osteoblasts in male mice, results in increased bone resorption and decreased structural integrity of the bone, leading to a reduction in trabecular bone volume at 32 weeks of age. These data provide evidence of a role for androgens in the maintenance of trabecular bone volume directly through DNA binding-dependent actions of the AR in mature osteoblasts.

Aging↗

PubMed2006

Severe combined hyperlipidaemia and retinal lipid infiltration in a patient with Type 2 diabetes mellitus.

Severe combined hyperlipidaemia has occasionally been associated with infiltration of tissues in addition to arteries and the skin. We report a woman with Type 2 diabetes mellitus (DM) and severe combined hyperlipidaemia who developed retinal lipid infiltration, resulting in blindness. A 61-year-old woman with a 15-year history of Type 2 DM was admitted following a two-week history of progressive visual loss. Examination identified lipid infiltration into the retina. Phenotypically she had severe combined hyperlipidaemia with elevated IDL cholesterol and a broad beta band on lipoprotein electrophoresis, raising the possibility of familial dysbetalipoproteinaemia. However, gene sequencing analysis indicated that the patient was homozygous for the E3/E3 allele of the ApoE gene with no mutations detected in either the coding region or intron-exon boundaries. Her lipid profile improved following dietary therapy and gemfibrozil treatment, but this had little effect on either her fundal appearances or her visual acuity. Type 2 DM plays a vital role both in allowing expression of severe combined hyperlipoproteinaemia, in addition to serving as a risk factor for complications such as tissue infiltration.

Aged↗

PubMed2006

Current and future approaches using genetically modified mice in endocrine research.

Genetically modified mouse models have been used widely to advance our knowledge in the field of endocrinology and metabolism. A number of different approaches to generate genetically modified mice are now available, which provide the power to analyze the role of individual proteins in vivo. However, there are a number of points to be considered in the use and interpretation of these models. This review discusses the advantages and disadvantages involved in the generation and use of different genetically modified mouse models in endocrine research, including conventional techniques (e.g., overexpression, knockout, and knock-in models), tissue- and/or time-specific deletion of target genes [e.g., Cre-loxP and short interfering (si)RNA transgenic approaches], and gene-trap approaches to undertake functional genomics. This review also highlights the many factors that should be considered when assessing the phenotype of these mouse models, many of which are relevant to all murine physiological studies. These approaches are a powerful means by which to dissect the function of genes and are revolutionizing our understanding of endocrine physiology and metabolism.

Animals↗

PubMed2005

Effects of estradiol and dihydrotestosterone on osteoblast gene expression in osteopenic ovariectomized rats.

Because androgens increase bone formation and estrogens inhibit bone resorption, there is a potential therapeutic use for a combined treatment of these hormones to preserve bone. We investigated the effect of dihydrotestosterone (DHT) and estradiol, alone and in combination, on the mRNA levels of genes expressed during osteoblast development in osteopenic ovariectomized (ovx) rats: 40 animals were ovx and administered vehicle or 80 mg/kg body weight DHT at 15 weeks postovariectomy. At 19 weeks postovariectomy, the rats were administered vehicle or 20 mg/kg body weight estradiol for 1 week. The treatment groups were as follows: (1) vehicle + vehicle, (2) DHT + vehicle, (3) vehicle + estradiol, and (4) DHT + estradiol. Fasting blood and urine samples were collected at 15, 17, 19, and 20 weeks postovariectomy for bone biochemical analyses. On completion of both procedures, the long bones were removed and total RNA extracted. Combined DHT and estradiol treatment increased the mRNA (P < 0.001) and serum levels of alkaline phosphatase (ALP) (P < 0.01) compared to control rats. These data suggest that combined DHT and estradiol treatment stimulates osteoblasts at an early stage of their development when ALP is expressed.

Animals↗

PubMed2005

The effects of salmon calcitonin-induced hypocalcemia on bone metabolism in ovariectomized rats.

The ovariectomized rat has proved to be a most useful model for preclinical testing of potential therapies for osteoporosis. We describe the immediate effects of a single treatment with salmon calcitonin (sCT) on calcium homeostasis and bone turnover markers in 6-month-old sham and ovariectomized (ovx) rats at 15 days postovariectomy. Rats were fasted for 24 h prior to and following administration of 0.3 microg/kg body weight sCT. Blood specimens were collected at 0 (pretreatment), 2, 4, and 8 h. Urine samples were collected during the intervening periods. sCT treatment produced a decrease in blood ionized calcium at 2 h posttreatment in sham and ovx rats (P < 0.001), which was exaggerated in the ovx rats (P < 0.001). Increased parathyroid hormone (PTH) levels (P < 0.001) accompanied the hypocalcemia in ovx rats. Furthermore, PTH levels were significantly higher in ovx rats compared with sham rats for the same ionized calcium range of 1.275-1.300 mmol/l (P < 0.05). sCT treatment in sham rats increased urine hydroxyproline (UHyp) at 6 h posttreatment (P < 0.01). In conclusion, the calcitonin-induced hypocalcemia and secondary hyperparathyroidism was more pronounced in the ovariectomized rats, consistent with the actions of calcitonin in states of increased bone turnover induced by estrogen deficiency. This study highlights the importance of considering the actions of PTH and estrogen status when interpreting changes in calcium homeostasis and bone turnover following treatment with calcitonin in rodent models and provides further evidence for a potential role of estrogen in parathyroid function.

Animals↗

PubMed2004

Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo.

Amylin is a member of the calcitonin family of hormones cosecreted with insulin by pancreatic beta cells. Cell culture assays suggest that amylin could affect bone formation and bone resorption, this latter function after its binding to the calcitonin receptor (CALCR). Here we show that Amylin inactivation leads to a low bone mass due to an increase in bone resorption, whereas bone formation is unaffected. In vitro, amylin inhibits fusion of mononucleated osteoclast precursors into multinucleated osteoclasts in an ERK1/2-dependent manner. Although Amylin +/- mice like Amylin-deficient mice display a low bone mass phenotype and increased bone resorption, Calcr +/- mice display a high bone mass due to an increase in bone formation. Moreover, compound heterozygote mice for Calcr and Amylin inactivation displayed bone abnormalities observed in both Calcr +/- and Amylin +/- mice, thereby ruling out that amylin uses CALCR to inhibit osteoclastogenesis in vivo. Thus, amylin is a physiological regulator of bone resorption that acts through an unidentified receptor.

Amyloid↗

PubMed2004

Genetically modified animal models as tools for studying bone and mineral metabolism.

Genetic modification of mice is a powerful tool for the study of bone development and metabolism. This review discusses the advantages and disadvantages of various approaches used in bone-related research and the contributions these studies have made to bone biology. Genetic modification of mice is a powerful tool for the study of bone development and metabolism. This review discusses the advantages and disadvantages of various approaches used in bone-related research and the contributions these studies have made to bone biology. The approaches to genetic modification included in this review are (1) overexpression of genes, (2) global gene knockouts, (3) tissue-specific gene deletion, and (4) gene knock-in models. This review also highlights issues that should be considered when using genetically modified animal models, including the rigorous control of genetic background, use of appropriate control lines, and confirmation of tissue specificity of gene expression where appropriate. This technology provides a unique and powerful way to probe the function of genes and is already revolutionizing our approach to understanding the physiology of bone development and metabolism.

Animals↗

PubMed2004

Effects of dihydrotestrone on osteoblast gene expression in osteopenic ovariectomized rats.

Androgens stimulate bone formation, however, the precise mechanism of androgen action on osteoblasts remains to be elucidated. In this study, we defined the expression profile of osteoblast genes in ovariectomized rats with established osteopenia and their response to treatment with dihydrotestosterone (DHT). Twenty-four, 8-month-old female Sprague-Dawley rats were ovariectomized (ovx) and were administered vehicle, 40 mg, 80 mg, or 160 mg/kg body weight DHT at 15-weeks post-ovariectomy for 14 weeks. Alkaline phosphatase (ALP) messenger ribonucleic acid (mRNA) levels were increased at 29-weeks post-ovariectomy compared with preoperative rats (P < 0.05). In contrast, osteopontin and osteocalcin mRNA levels were unchanged. Treatment of osteopenic ovx rats with DHT for 14 weeks suppressed the ovariectomy-induced increase in ALP (P < 0.05) mRNA levels, independent of dose. These data suggest that androgens may act to inhibit the stimulation of the early stages of osteoblast development that occurs in the absence of estrogen and in states of low bone turnover.

Alkaline Phosphatase↗