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Bone morphogenetic proteins (BMPs) function during various aspects of embryonic development including skeletogenesis. However, their biological functions after birth are less understood. To investigate the role of BMPs during bone remodeling, we generated a postnatal osteoblast-specific disruption of Bmpr1a that encodes the type IA receptor for BMPs in mice. Mutant mice were smaller than controls up to 6 months after birth. Irregular calcification and low bone mass were observed, but there were normal numbers of osteoblasts. The ability of the mutant osteoblasts to form mineralized nodules in culture was severely reduced. Interestingly, bone mass was increased in aged mutant mice due to reduced bone resorption evidenced by reduced bone turnover. The mutant mice lost more bone after ovariectomy likely resulting from decreased osteoblast function which could not overcome ovariectomyinduced bone resorption. In organ culture of bones from aged mice, ablation of the Bmpr1a gene by adenoviral Cre recombinase abolished the stimulatory effects of BMP4 on the expression of lysosomal enzymes essential for osteoclastic bone resorption. These results demonstrate essential and age-dependent roles for BMP signaling mediated by BMPRIA (a type IA receptor for BMP) in osteoblasts for bone remodeling.Bone formation is a well characterized process; however, little is known about the molecular mechanisms that regulate bone remodeling, the physiological process through which bone mass is maintained constant. Remodeling consists of two distinct phases: initial bone resorption by the osteoclasts, followed by de novo bone formation by the osteoblasts (1). Differentiated osteoblasts are the only cells responsible for bone formation. Bone formation is thought to be regulated by hormones and by locally acting growth factors (2). Bone morphogenetic proteins (BMPs) 1 are secreted molecules and members of transforming growth factor-␤ superfamily (3, 4). They were discovered by their ectopic bone formation activity when implanted locally in soft tissues (5). Over the past decade, the phenotypes of mice with mutations in genes coding for this group of proteins and their receptors uncovered the essential roles for BMPs in wide variety of developmental processes, including skeletal development and patterning (6 -9). However, despite its powerful ability to induce ectopic osteogenesis, the essential role of BMPs in bone formation and bone metabolism in the adult skeleton has not been established (10) because of embryonic lethality resulting from mutations of genes encoding the most potent BMPs for bone formation, BMP2 and BMP4, and their receptors (11-13). We previously generated a null allele for Bmpr1a that encodes a type IA receptor for BMP (BMPRIA or ALK3). Mice homozygous for this null allele died by embryonic day 8.0 (E8.0) without mesoderm formation (13). Bmpr1a is expressed in most tissues throughout development and after birth (13,14). Expression of a dominant-negative form of BMPRIA in a cultured cell line or chick limb buds suggests ...

CuO nanospheres, synthesized by a simple one-step hydrothermal method, have been applied to modify the glassy carbon (GC) electrode for sensitive nonenzymatic glucose detection. The CuO nanospheres modified electrode, compared to the Nafion modified GC electrode, exhibits an enhanced electrocatalytic property for direct glucose oxidation and shows a fast response and a high sensitivity for the amperometric detection of glucose. It has been determined that the dissolved oxygen is not involved in glucose oxidation and the high concentration of NaCl does not poison the electrode. These results also indicate that CuO nanospheres have great potential application in electrochemical detection.Keywords: Cupric oxide, Nanospheres, Nonenzymatic, Oxidation, Glucose DOI: 10.1002/elan.200804327 Diabetes is a metabolic disorder and a major world health problem. There are over 170 million diabetics worldwide (WHO 2004) and the number is projected to 300 million in 2025, so glucose detection is becoming incredibly important to the patients suffering from diabetes [1,2]. Due to its high sensitivity and selectivity to glucose and stable activity over a broad range of pH [3], glucose oxidase (GOx) has been widely used to construct various amperometric biosensors for glucose detection [1, 4 -12]. However, due to the intrinsic feature of enzymes, GOx-based biosensors suffer from a stability problem [13]. In recent years, considerable attention has been paid to develop enzyme-free electrodes [14 -19]. Precious metals [14,15,17,20], metal alloys [18,21], and metal nanoparticles [16, 22 -24] have been extensively investigated in the development of nonenzymatic glucose sensors. However, these electrodes have drawbacks such as low sensitivity and costliness, and also suffer from the poisoning of chloride ions [15,19,25], thus, their application is greatly limited. Therefore, the development of a cost-effective, sensitive, and reliable enzyme-free glucose sensor is still greatly demanded [13].Cupric oxide (CuO), a p-type semiconductor with a narrow band gap of 1.2 eV, has been studied intensely because of its numerous applications in catalysis, semiconductors, batteries, gas sensors, biosensors, and field transistors [26 -32]. CuO-carbon black modified composite and CuO-coated glass beads have been reported for the detection of glucose, but their application is limited by the tedious fabrication processes [33,34]. With the development of nanotechnology, nanostructured CuO is promising in the development of nonenzymatic glucose sensors because of its highly specific surface area, good electrochemical activity, and the possibility of promoting electron transfer reactions at a lower overpotential. Previous attempts to utilize CuO nanomaterials for the amperometric detection of glucose are limited. Recently Zhuang et al. reported CuO nanowires synthesized on a Cu rod for glucose detection [25]. The developed sensor is elegant and shows an improved sensitivity. However, the synthesis of CuO nanowires is still tedious and involves mu...

The androgen receptor (AR), when complexed with 5␣-dihydrotestosterone (DHT), supports the survival and proliferation of prostate cells, a process critical for normal development, benign prostatic hypertrophy, and tumorigenesis. However, the androgen-responsive genetic pathways that control prostate cell division and differentiation are largely unknown. To identify such pathways, we examined gene expression in the ventral prostate 6 and 24 h after DHT administration to androgen-depleted rats. 234 transcripts were expressed significantly differently from controls (p < 0.05) at both time points and were subjected to extensive data mining. Functional clustering of the data reveals that the majority of these genes can be classified as participating in induction of secretory activity, metabolic activation, and intracellular signaling/signal transduction, indicating that AR rapidly modulates the expression of genes involved in proliferation and differentiation in the prostate. Notably AR represses the expression of several key cell cycle inhibitors, while modulating members of the wnt and notch signaling pathways, multiple growth factors, and peptide hormone signaling systems, and genes involved in MAP kinase and calcium signaling. Analysis of these data also suggested that p53 activity is negatively regulated by AR activation even though p53 RNA was unchanged. Experiments in LNCaP prostate cancer cells reveal that AR inhibits p53 protein accumulation in the nucleus, providing a post-transcriptional mechanism by which androgens control prostate cell growth and survival. In summary these data provide a comprehensive view of the earliest events in AR-mediated prostate cell proliferation in vivo, and suggest that nuclear exclusion of p53 is a critical step in prostate growth.

The androgen receptor (AR), as a classic steroid receptor, generally mediates biologic responses to androgens. In bone tissue, both AR and the estrogen receptor (ER) are expressed in a variety of cell types. Because androgens can be converted into estrogen via aromatase activity, the specific role of the AR in maintenance of skeletal homoeostasis remains controversial. The goal of this study was to use skeletally targeted overexpression of AR as a means of elucidating the specific role(s) for AR transactivation in bone homeostasis. Rat AR cDNA was cloned downstream of a 3.6-kb alpha1(I)-collagen promoter fragment and used to create AR-transgenic mice. AR-transgenic males gain less weight and body and femur length is shorter than wild-type controls, whereas females are not different. AR-transgenic males also demonstrate thickened calvaria and increased periosteal but reduced endosteal labeling by fluorescent labeling and reduced osteocalcin levels. High-resolution micro-computed tomography shows normal mineral content in both male and female AR-transgenic mice, but male AR-transgenics reveal a reduction in cortical area and moment of inertia. Male AR-transgenics also demonstrate an altered trabecular morphology with bulging at the metaphysis. Histomorphometric analysis of trabecular bone parameters confirmed the increased bone volume comprised of more trabeculae that are closer together but not thicker. Biomechanical analysis of the skeletal phenotype demonstrate reduced stiffness, maximum load, post-yield deflection, and work-to-failure in male AR-transgenic mice. Steady-state levels of selected osteoblastic and osteoclastic genes are reduced in tibia from both male and female transgenics, with the exception of increased osteoprotegerin expression in male AR-transgenic mice. These results indicate that AR action is important in the development of a sexually dimorphic skeleton and argue for a direct role for androgen transactivation of AR in osteoblasts in modulating skeletal development and homeostasis.