Effects of the Lysine Methyltransferase Inhibitor AZ505 on Bone Metabolism

Background@#Protein methylation has important role in regulating diverse cellular responses, including differentiation, by affecting protein activity, stability, and interactions. AZ505 is an inhibitor of the SET and MYND domain-containing protein 2 lysine methylase. In this study, we investigated the effect of AZ505 on osteoblast and osteoclast differentiation in vitro and evaluated the effect of AZ505 in vivo on the long bones in mice. @*Methods@#Osteoblast differentiation was assessed by alkaline phosphatase (ALP) and Alizarin red staining after culturing calvarial preosteoblasts in an osteogenic medium. Osteoclast differentiation was analyzed by tartrate-resistant acid phosphatase (TRAP) staining in bone marrow-derived macrophages cultured with macrophage-colony stimulating factor and receptor activator of nuclear factor-κB ligand (RANKL). For in vivo experiments, mice were intraperitoneally injected with AZ505 and femurs were examined by micro-computed tomography. @*Results@#AZ505 increased ALP and Alizarin red staining in cultured osteoblasts and the expression of osteoblast marker genes, including Runx2 and osteocalcin. AZ505 resulted in decreased TRAP-staining of osteoclasts and expression of c-Fos and nuclear factor of activated T cells transcription factors and osteoclast marker genes, including cathepsin K and dendritic cell-specific transmembrane protein. Unexpectedly, in vivo administration of AZ505 markedly decreased the trabecular bone mass of femurs. In support of this catabolic result, AZ505 strongly upregulated RANKL expression in osteoblasts. @*Conclusions@#The results indicate that AZ505 has a catabolic effect on bone metabolism in vivo despite its anabolic effect in bone cell cultures. The findings indicate that cell culture data should be extrapolated cautiously to in vivo outcomes for studying bone metabolism.

Adseverin mediates RANKL-induced osteoclastogenesis by regulating NFATc1

Adseverin is a Ca2+-dependent actin filament-severing protein that has been reported to regulate exocytosis via rearrangements of the actin cytoskeleton in secretory cells. However, the role of adseverin in bone cells has not yet been well characterized. Here, we investigated the role of adseverin in osteoclastogenesis using primary osteoclast precursor cells. Adseverin expression was upregulated during RANKL (receptor activator of nuclear factor-kappaB ligand)-induced osteoclast differentiation. Moreover, genetic silencing of adseverin decreased the number of osteoclasts generated by RANKL. Adseverin knockdown also suppressed the RANKL-mediated induction of nuclear factor of activated T-cell c1 (NFATc1), which is a key transcription factor in osteoclastogenesis. In addition, adseverin knockdown impaired bone resorption and the secretion of bone-degrading enzymes from osteoclasts. These effects were accompanied by decreased NFATc1 expression and the activation of nuclear factor-kappaB. Collectively, our results indicate that adseverin has a crucial role in osteoclastogenesis by regulating NFATc1.

Vitamin D intake, Outdoor Activity Time and Serum 25-OH Vitamin D Concentrations of Korean Postmenopausal Women by Season and by Age / 대한지역사회영양학회지

OBJECTIVES: The purpose of this study was to examine the relative impact of seasonal differences and age on dietary vitamin D intakes, outdoor activity time and serum vitamin D status among Korean postmenopausal women. METHODS: A cross-sectional study was conducted with 164 free-living postmenopausal women (mean age=55.4 years) in Daegu, Korea. Dietary intake, daily physical activity patterns and fasting blood samples were collected during summer and winter. We compared the results from 75 women during summer and 89 women during winter. Dietary intake of vitamin D was assessed by 24-hour recall method. Daily outdoor activity time was derived from physical activity diary. RESULTS: The average dietary intake of vitamin D of the participants was 3.7 microg during summer, 3.3 microg during winter, showing no significant difference between the two seasons. The average time spent on outdoor activities was not significantly different between summer (=35.1 +/- 75.0 min/d) and winter (=48.5 +/- 76.8 min/d). The average serum 25-(OH) vitamin D concentrations of participants was 17.5 +/- 7.5 ng/mL in the summer and 13.4 +/- 4.3 ng/mL in the winter, showing no significant differences by season. Dietary intake of vitamin D was not related to age. When total subjects were divided into two groups by age, the average serum 25-(OH) vitamin D concentration was significantly higher in older group (p=0.047) and time spent on outdoor activities was also (p=0.018) significantly higher in the older group. CONCLUSIONS: In order to improve the current vitamin D status of Korean postmenopausal women, nutrition education programs should focus more on adequate intake of vitamin D, while maintaining enough outdoor activities over the season.

Seasonal Differences in Outdoor Activity Time and Serum 25-(OH) Vitamin D Status of Korean Young Women / 대한지역사회영양학회지

OBJECTIVES: This study was intended to examine the seasonal differences in outdoor activity times and dietary vitamin D intakes, and explicates their relative impact on improving serum 25-(OH) vitamin D status among Korean young women. METHODS: A cross-sectional study was conducted with 135 free-living women aged 19-39 years in Daegu-Kyungbook, Korea. We compared the results from 52 women for the summer and 83 women for the winter. Dietary intake of vitamin D was assessed by 24 hour recall method for non-consecutive three days as well as by food frequency method. Daily outdoor activity times were derived from 24 hour physical activity diary. RESULTS: The average dietary intake of vitamin D of the participants by 24 hour recall method was 3.1 microg during the summer, 3.3 microg during the winter, showing no significant difference between the two seasons. Times spent on outdoor activities (p < 0.01) in the summer (= 23.8 +/- 23.6 min) were much longer than that in the winter (= 10.8 +/- 13.4 min). The serum 25-(OH) vitamin D levels of participants were 17.5 +/- 7.5 ng/mL in the summer and 13.4 +/- 4.3 ng/mL in the winter, showing that the latter was significantly lower than that of the former (p < 0.001). The serum 25-(OH) vitamin D levels of subjects were positively related to outdoor activities (r = 0.315, p < 0.05) during the summer, while related to dietary intake (r = 0.252, p < 0.05) during the winter. CONCLUSIONS: In order to improve the current vitamin D status of Korean young women, nutrition education programs should focus on increasing more dietary intake especially during the winter, and performing more outdoor activities in other seasons.

Hemoglobin A1c in the Screening of Obesity-Related Diseases in Children and Adolescents

PURPOSE: The aim of this study is to investigate differences in hemoglobin A1c (HbA1c) levels according to degree of obesity, clinical findings on HbA1c 5.7% and factors affecting HbA1c in growing children and adolescents. METHODS: 168 children and adolescents (M/F, 93/75; age, 10.2+/-2.6 years) who visited an obesity clinic were included in the study. Participant's body mass index (BMI), percent weight for height (PWH), height z score (HTZ), weight z score (WTZ), and BMI z score (BMIZ) were calculated. Their blood glucose, insulin, total cholesterol, triglyceride, HDL-cholesterol (HDL-C), aspartate aminotransferase (AST), alanine aminotransferase (ALT), insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) levels were checked. Confirmed cases of diabetes and endocrine disease were excluded. Participants were divided into two groups based on whether their HbA1c levels were higher or lower than 5.7%. The difference in HbA1c between the groups based on the BMIZ 2 and PWH 20 were analyzed. A correlation analysis involving HbA1c and metabolic parameters was conducted, and factors contributing to HbA1c were evaluated through a regression analysis. RESULTS: HbA1c was higher in subjects with impaired fasting glucose (5.3+/-0.3, 5.4+/-0.2; P = 0.018). HbA1c and the homeostasis model assessment of insulin resistance (HOMA-IR) were not significantly different in the groups based on BMIZ 2.0. Based on PWH 20, HOMA-IR was significantly different (1.8+/-0.7, 2.3+/-1.1; P < 0.05), although HbA1c was not. Levels of TG (107.4+/-69.4, 154.1+/-77.7; P = 0.006), HDL-C (53.6+/-11.9, 47.4+/-6.6; P = 0.024), AST (29.7+/-11.4, 39.2+/-24.6; P = 0.004), and ALT (32.4+/-32.0, 53.9+/-58.8; P = 0.014) indicated significant differences between the groups. There were positive correlations between HbA1c and height, weight, BMI, gender, AST, ALT, glucose, and HOMA-IR, but no significant correlation with HTZ, WTZ, and BMIZ. The contributing factors for HbA1c were gender, ALT, BMI, and IGFBP-3. CONCLUSIONS: HbA1c level is associated with metabolic syndrome parameters, but is not correlated with degree of obesity. Along with HbA1c, other factors should be considered in evaluating the risk of complications related to obesity in children and adolescents.

Hemoglobin A1c in the Screening of Obesity-Related Diseases in Children and Adolescents

PURPOSE: The aim of this study is to investigate differences in hemoglobin A1c (HbA1c) levels according to degree of obesity, clinical findings on HbA1c 5.7% and factors affecting HbA1c in growing children and adolescents. METHODS: 168 children and adolescents (M/F, 93/75; age, 10.2+/-2.6 years) who visited an obesity clinic were included in the study. Participant's body mass index (BMI), percent weight for height (PWH), height z score (HTZ), weight z score (WTZ), and BMI z score (BMIZ) were calculated. Their blood glucose, insulin, total cholesterol, triglyceride, HDL-cholesterol (HDL-C), aspartate aminotransferase (AST), alanine aminotransferase (ALT), insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) levels were checked. Confirmed cases of diabetes and endocrine disease were excluded. Participants were divided into two groups based on whether their HbA1c levels were higher or lower than 5.7%. The difference in HbA1c between the groups based on the BMIZ 2 and PWH 20 were analyzed. A correlation analysis involving HbA1c and metabolic parameters was conducted, and factors contributing to HbA1c were evaluated through a regression analysis. RESULTS: HbA1c was higher in subjects with impaired fasting glucose (5.3+/-0.3, 5.4+/-0.2; P = 0.018). HbA1c and the homeostasis model assessment of insulin resistance (HOMA-IR) were not significantly different in the groups based on BMIZ 2.0. Based on PWH 20, HOMA-IR was significantly different (1.8+/-0.7, 2.3+/-1.1; P < 0.05), although HbA1c was not. Levels of TG (107.4+/-69.4, 154.1+/-77.7; P = 0.006), HDL-C (53.6+/-11.9, 47.4+/-6.6; P = 0.024), AST (29.7+/-11.4, 39.2+/-24.6; P = 0.004), and ALT (32.4+/-32.0, 53.9+/-58.8; P = 0.014) indicated significant differences between the groups. There were positive correlations between HbA1c and height, weight, BMI, gender, AST, ALT, glucose, and HOMA-IR, but no significant correlation with HTZ, WTZ, and BMIZ. The contributing factors for HbA1c were gender, ALT, BMI, and IGFBP-3. CONCLUSIONS: HbA1c level is associated with metabolic syndrome parameters, but is not correlated with degree of obesity. Along with HbA1c, other factors should be considered in evaluating the risk of complications related to obesity in children and adolescents.

Evaluation of kidney size in children: a pilot study of renal length as a surrogate of organ growth / 소아과

PURPOSE: Somatic growth is an important indicator of health in children. Adequate organ growth is essential in growth and directly related to body growth. We consider renal length as a surrogate of organ growth in growing children. Measurement of weight, height, and many anthropometric indices, such as body surface area (BSA), body mass index (BMI), and Rohrer and Kaup indices, are used to evaluate growth status. The aim of this study was to evaluate the association between renal length and somatic parameters and analyze the affecting factors for renal size during growth. METHODS: The data for renal length in 66 children (age, 12.9+/-15.6 months; male/female, 34/32) were obtained. Each kidney was measured with ultrasonography and dimercaptosuccinic acid scan. The data on age, sex, height, and weight were obtained from the medical records. BSA, BMI, and Rohrer and Kaup indices were calculated from measured height and weight. BSA was calculated by 2 methods, and is expressed as BSA I and BSA II. RESULTS: There were significant correlations between renal size and age, weight, height, BSA I, BSA II, and Rohrer index. In the regression analysis, the most significant contributing factor to renal growth was height (R2=0.636, P<0.001). CONCLUSION: Height seems to be the most important factor associated with organ growth in growing children. Further studies to evaluate adequate organ growth should be carried out.

Evaluation of kidney size in children: a pilot study of renal length as a surrogate of organ growth / 소아과

PURPOSE: Somatic growth is an important indicator of health in children. Adequate organ growth is essential in growth and directly related to body growth. We consider renal length as a surrogate of organ growth in growing children. Measurement of weight, height, and many anthropometric indices, such as body surface area (BSA), body mass index (BMI), and Rohrer and Kaup indices, are used to evaluate growth status. The aim of this study was to evaluate the association between renal length and somatic parameters and analyze the affecting factors for renal size during growth. METHODS: The data for renal length in 66 children (age, 12.9+/-15.6 months; male/female, 34/32) were obtained. Each kidney was measured with ultrasonography and dimercaptosuccinic acid scan. The data on age, sex, height, and weight were obtained from the medical records. BSA, BMI, and Rohrer and Kaup indices were calculated from measured height and weight. BSA was calculated by 2 methods, and is expressed as BSA I and BSA II. RESULTS: There were significant correlations between renal size and age, weight, height, BSA I, BSA II, and Rohrer index. In the regression analysis, the most significant contributing factor to renal growth was height (R2=0.636, P<0.001). CONCLUSION: Height seems to be the most important factor associated with organ growth in growing children. Further studies to evaluate adequate organ growth should be carried out.

Body Composition Analysis in Newly Diagnosed Diabetic Adolescent Girls / 대한소아내분비학회지

PURPOSE: The objective of this study was to determine the type differences of diabetes by analyzing the growth status and body composition of newly diagnosed diabetic adolescent girls. METHODS: The study included 6 type 1 diabetic adolescent girls (age 11.7 +/- 1.9 years) and 6 type 2 diabetic adolescent girls (age 14.4 +/- 2.6 years). The height, weight and body composition of fat mass and fat-free mass were measured in each patient. Body mass index (BMI), fat mass index (FMI), fat free mass index (FFMI) and percent body fat (PBF) were calculated and each component was plotted on a body composition chart. RESULTS: Type 2 diabetic adolescent girls seemed to be taller and heavier compared to type 1 diabetic girls, but the differences in height and weight z-score were not significant. BMI, FFMI, FMI, PBF were also higher in type 2 diabetic girls. The body composition chart revealed that type 2 diabetic girls had significantly higher FMI and PBF. In type 1 diabetic girls, FFMI was lower compared to type 2 diabetic girls. The BMI difference between diabetes types was explained with the difference in FFMI as well as FMI. CONCLUSION: The components of body composition differ according to diabetes type in adolescent girls. Measuring the body composition of diabetic girls might help to promote growth and adequate FFM gain during childhood. In diabetes control, diet and exercise should be emphasized along with insulin treatment.