Sclerostin antibody (Scl-Ab) increases osteoblast activity, in part through increasing modeling-based bone formation on previously quiescent surfaces. Histomorphometric studies have suggested that this might occur through conversion of bone lining cells into active osteoblasts. However, direct data demonstrating Scl-Ab-induced conversion of lining cells into active osteoblasts is lacking. Here, we used in vivo lineage tracing to determine if Scl-Ab promotes the conversion of lining cells into osteoblasts on periosteal and endocortical bone surfaces in mice. Two independent, tamoxifen-inducible lineage tracing strategies were used to label mature osteoblasts and their progeny using the DMP1 and osteocalcin promoters. Following a prolonged ‘chase’ period, the majority of labeled cells on bone surfaces assumed a thin, quiescent morphology. Then, mice were treated with either vehicle or Scl-Ab (25 mg/kg) twice over the course of the subsequent week. After sacrifice, marked cells were enumerated, their thickness quantified, and proliferation and apoptosis examined. Scl-Ab led to a significant increase in the average thickness of labeled cells on periosteal and endocortical bone surfaces, consistent with osteoblast activation. Scl-Ab did not induce proliferation of labeled cells, and Scl-Ab did not regulate apoptosis of labeled cells. Therefore, direct reactivation of quiescent bone lining cells contributes to the acute increase in osteoblast numbers following Scl-Ab treatment in mice.

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Our data indicate that the R65L polymorphism of the GRK4 gene plays a role in BP regulation in adolescents and young adults.

As Helicobacter pylori (HP) is a Gram-negative bacterium, we investigated the associations between several functional polymorphisms in genes involved in lipopolysaccharide (LPS) signaling and the prevalence of various stages of gastric premalignant lesions in a Venezuelan population. The two NOD2 polymorphisms, del3020insC and Gly908Arg, were too infrequent to study their associations with gastric lesions. The risk of intestinal metaplasia (IM) was significantly increased among subjects with the CD14 T-260 allele compared to those without this allele. A similar, but nonsignificant increase in risk for dysplasia was observed among homozygotes of this allele. There was no association between TLR4 Asp299Gly polymorphism and any type of lesions, except for a slight nonsignificant increase in risk of IM associated with the AA genotype among subjects with a higher histological HP score. These results suggest that genetic polymorphisms in HP LPS signaling may be implicated in the development of intermediate stages of gastric premalignant lesions.

Approximately 20 -40% of adolescents have shown a reduction of urinary sodium excretion (U Na V) in response to blood pressure (BP) increase during behavioral stress. G protein-coupled receptor kinase 4 (GRK4) mediates the pressure and natriuresis relation. The present study investigated the impact of GRK4 genetic variants on U Na V under stress. A total of 664 normotensive adolescents including whites and blacks (17.6 Ϯ 3.3 yrs, 43.4% blacks) were recruited. Participants were subjected to a stress-protocol including three 10-min tasks (a social competence interview, a virtual reality car driving simulation test, and a video game challenge), concluded by a urine collection. Three functional polymorphisms including R65L, A142V and A486V were genotyped. Given blacks compared with whites had significantly higher systolic BP (SBP) levels during rest (p Ͻ 0.001) and stress (p Յ 0.001), there was no statistical difference in U Na V in response to stress between the two ethnic groups. In blacks, compared with R65R homozygotes, individuals with R65L or L65L genotype had significantly lower levels of stress-induced U Na V (8.42 Ϯ 0.63 versus 9.85 Ϯ 0.37 mEq/h, p ϭ 0.01). In summary, BP elevation seems uncoupled with U Na V increase during behavioral stress in black adolescents. The 65L allele of the GRK4 gene is associated with stress-induced U Na V reduction, suggesting impaired sodium handling in affected black youth. E ssential hypertension is determined by gene and environment interactions, and has its origin in childhood. Blood pressure (BP) increase during a sustained period of behavioral stress is typically accompanied by a compensatory increase in urinary sodium excretion (U Na V) (1,2). Our previous data show that an inadequate compensatory increase in U Na V in response to stress occurs in 20 -40% of adolescents aged 15-19 y (Harshfield et al. Annual Meeting of Society of Behavioral Medicine, April 13-16, 2005, Boston), which may predict the development of hypertension (1,2). In particular, we have recently demonstrated that U Na V in response to stress is a heritable phenotype in a multi-ethnic cohort of adolescents (Ge et al., Annual meeting of the American Society of Human Genetics, October 25-29, 2005, Salt Lake City). However, no candidate gene association study has been performed to date. Dopamine enhances renal sodium excretion, diuresis and natriuresis via dopamine receptors D (DRD) in the renal proximal tubules (3-5). G protein-coupled receptor kinase 4 (GRK4) regulates DRD1 phosphorylation, desensitization and internalization (6,7). Although functional single nucleotide polymorphisms (SNPs) of the GRK4 gene have been associated with hypertension in adult populations (8 -11), the impact of these variants on sodium homeostasis in humans remains unknown. Thus we conducted association analyses of the GRK4 polymorphisms in relation to stress-induced U Na V in a sample of young normotensive white and black twins. METHODS Study population.A total of 664 normotensive twin subjects including whites a...

While the results of the present study suggest roles of genetic variability in these anti-inflammatory mediators in different stages of gastric carcinogenesis, there is high likelihood that they were chance findings due to multiple comparisons.

The sympathetic nervous system (SNS) is the first line of defense in the response to environmental stress through its regulation of second-to-second changes in blood pressure (BP). Both the activity of the SNS and the therapeutic responses to SNS agonists and antagonists are known to be highly variable in the population. "Small" changes caused by single nucleotide polymorphisms (SNPs) of SNS genes may have considerable impact on SNS function and individualized hypertension treatment. In this review, we first describe the physiology of the SNS and its influence on cardiovascular and renal mechanisms of BP regulation. A thorough review of the role of genetic variability of various SNS genes in relation to the development of BP and essential hypertension (EH) follows. Given the vast number of SNS components, evaluations of multiple SNPs from multiple SNS genes are necessary for future association studies of BP and EH. One way to surpass the limitations and inconsistencies of previous association studies is to use a gene-based approach also referred to as indirect association, which takes all common variation within a candidate gene into account. In order to determine how SNS genes are differentially expressed or silenced, activated or inactivated against various environmental backgrounds, it is important to assess not only environmental and lifestyle risk factors such as diet, climate, chronic stress, but also personality characteristics such as hostility and coping styles. Uncovering relevant gene-gene and gene-environment interactions within the SNS cascade will not only enable early detection of EH risk but will also aid in the treatment of hypertensives through both non-pharmacological and pharmacological means.