Yumie Rhee

Vitamin D Insufficiency in Korea—A Greater Threat to Younger Generation: The Korea National Health and Nutrition Examination Survey (KNHANES) 2008

CONTEXT Vitamin D status in the Korean population has not been adequately determined. OBJECTIVE To investigate the vitamin D status and the prevalence of vitamin D insufficiency in the Korean population, and also identify the predictors for vitamin D insufficiency in Korea. DESIGN AND SETTING The Fourth Korea National Health and Nutrition Examination Surveys (KNHANES IV) in the Korean population conducted in 2008. PARTICIPANTS 3,047 males and 3,878 females aged 10 years and older selected in all the 16 administrative districts of South Korea. MAIN OUTCOME MEASURES Serum 25-hydroxyvitamin D [25(OH)D] levels and the prevalence of vitamin D insufficiency defined as serum 25(OH)D level of less than 20 ng/ml. RESULTS Vitamin D insufficiency was found in 47.3% of males and 64.5% of females, whereas only 13.2% of male and 6.7% of female population had a serum 25(OH)D level of greater than 30 ng/ml. Vitamin D insufficiency was most prevalent in the age of 20-29, with a rate of 65.0% in males and 79.9% in females, and least prevalent in the age of 60-69 in males and 50-59 in females. Those who work usually indoors were more predisposed to vitamin D insufficiency. In the adult population, predictors for vitamin D insufficiency included young age groups, spring and winter seasons, living in an urban area, and indoor occupations. CONCLUSIONS Vitamin D insufficiency is very common, and it is now a greater threat to the younger generation in Korea. Current recommendations for vitamin D intakes for Koreans are inadequate, especially for the youth.

miR-182 is a negative regulator of osteoblast proliferation, differentiation, and skeletogenesis through targeting FoxO1

Uncontrolled oxidative stress impairs bone formation and induces age‐related bone loss in humans. The FoxO family is widely accepted to play an important role in protecting diverse cells from reactive oxygen species (ROS). Activation of FoxO1, the main FoxO in bone, stimulates proliferation and differentiation as well as inhibits apoptosis of osteoblast lineage cells. Despite the important role of FoxO1, little is known about how FoxO1 expression in bone is regulated. Meanwhile, several recent studies reported that microRNAs (miRNAs) could play a role in osteoblast differentiation and bone formation by targeting various transcriptional factors. Here, we identified one additional crucial miRNA, miR‐182, which regulates osteoblastogenesis by repressing FoxO1 and thereby negatively affecting osteogenesis. Overexpression of miR‐182 in osteoblast lineage cells increased cell apoptosis and inhibited osteoblast differentiation, whereas in vivo overexpression of miR‐182 in zebrafish impaired bone formation. From in silico analysis and validation experiments, FoxO1 was identified as the target of miR‐182, and restoration of FoxO1 expression in miR‐182–overexpressing osteoblasts rescued them from the inhibitory effects of miR‐182. These results indicate that miR‐182 functions as a FoxO1 inhibitor to antagonize osteoblast proliferation and differentiation, with a subsequent negative effect on osteogenesis. To treat bone aging, an antisense approach targeting miR‐182 could be of therapeutic value.

Oncogenic osteomalacia associated with mesenchymal tumour detected by indium‐111 octreotide scintigraphy

In a 40‐year‐old man who had suffered from vague and generalized bone pains for 7 years due to oncogenic osteomalacia, the causative tumour was finally detected by Indium‐111 octreotide scintigraphy. Some characteristics of the tumour associated with oncogenic osteomalacia, such as its size, growth rate, location and origin, often make the diagnosis difficult. However, the recent discovery of somatostatin receptors in mesenchymal tumours, which are the most common cause of oncogenic osteomalacia, has raised the possibility of early detection of this devastating disorder. Here, we report that radiolabelled octreotide scintigraphy has a potential role as a diagnostic tool in oncogenic osteomalacia. However, the exact role of somatostatin receptors in tumours associated with oncogenic osteomalacia still remains elusive.

Low Serum Vitamin D Is Associated with High Risk of Diabetes in Korean Adults

Vitamin D may play a role in glucose metabolism. A low vitamin D level has been associated with increased risk of diabetes mellitus, but the association has not been confirmed in Asians. Our objective was to examine the association of serum 25-hydroxyvitamin D [25(OH)D] levels with insulin resistance and diabetes mellitus in Korean adults based on a large population-based survey. Cross-sectional analyses were carried out on 5787 Korean adults (2453 men and 3334 women) who were 20 y or older and participated in the Fourth Korea NHANES conducted in 2008. Diabetes mellitus was defined as fasting plasma glucose ≥7 mmol/L or current use of oral hypoglycemic agents or insulin. Insulin resistance was estimated by homeostatic model assessment for insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI). Compared to individuals with a sufficient serum 25(OH)D concentration ≥75 nmol/L, the OR (95% CI) for diabetes mellitus were 1.73 (1.09-2.74), 1.30 (0.91-1.84), and 1.40 (0.99-1.98) for serum 25(OH)D concentrations <25, 25 to <50, and 50 to <75 nmol/L, respectively, after multiple adjustments (P-trend < 0.0001). Furthermore, the serum 25(OH)D level was inversely associated with HOMA-IR (β = -0.061; P = 0.001) and positively associated with QUICKI (β = 0.059; P = 0.001) in overweight or obese participants. In conclusion, a low serum vitamin D concentration is associated with a high risk of diabetes mellitus in Korean adults and the concentration is inversely associated with insulin resistance in those who are overweight or obese.

Peripheral Effect of α-Melanocyte-stimulating Hormone on Fatty Acid Oxidation in Skeletal Muscle

To study the peripheral effects of melanocortin on fuel homeostasis in skeletal muscle, we assessed palmitate oxidation and AMP kinase activity in α-melanocyte-stimulating hormone (α-MSH)-treated muscle cells. After α-MSH treatment, carnitine palmitoyltransferase-1 and fatty acid oxidation (FAO) increased in a dose-dependent manner. A strong melanocortin agonist, NDP-MSH, also stimulated FAO in primary culture muscle cells and C2C12 cells. However, [Glu6]α-MSH-ND, which has ample MC4R and MC3R agonistic activity, stimulated FAO only at high concentrations (10–5 m). JKC-363, a selective MC4R antagonist, did not suppress α-MSH-induced FAO. Meanwhile, SHU9119, which has both antagonistic activity on MC3R and MC4R and agonistic activity on both MC1R and MC5R, increased the effect of α-MSH on FAO in both C2C12 and primary muscle cells. Small interference RNA against MC5R suppressed the α-MSH-induced FAO effectively. cAMP analogues mimicked the effect of α-MSH on FAO, and the effects of both α-MSH and cAMP analogue-mediated FAO were antagonized by a protein kinase A inhibitor (H89) and a cAMP antagonist ((Rp)-cAMP). Acetyl-CoA carboxylase activity was suppressed by α-MSH and cAMP analogues by phosphorylation through AMP-activated protein kinase activation in C2C12 cells. Taken together, these results suggest that α-MSH increases FAO in skeletal muscle, in which MC5R may play a major role. Furthermore, these results suggest that α-MSH-induced FAO involves cAMP-protein kinase A-mediated AMP-activated protein kinase activation.

Expression and Regulation of Osteoprotegerin in Adipose Tissue

Purpose Osteoprotegerin (OPG), a potent inhibitor of osteoclastic bone resorption, has a variety of biological functions that include anti-inflammatory effects. Adipocytes and osteoblasts share a common origin, and the formation of new blood vessels often precedes adipogenesis in developing adipose tissue microvasculature. We examined whether OPG is secreted from adipocytes, therefore contributing to the prevention of neovascularization and protecting the vessels from intimal inflammation and medial calcification. Materials and Methods The mRNA expression of OPG and receptor activator of NF-κB ligand (RANKL) was measured in differentiated 3T3L1 adipocytes and adipose tissues. Results OPG mRNA expression increased with the differentiation of 3T3L1 adipocytes, while RANKL expression was not significantly altered. OPG mRNA was expressed at higher levels in white adipose tissue than in brown adipose tissue and was most abundant in the epididymal portion. In differentiated 3T3L1 adipocytes, Rosiglitazone and insulin reduced the OPG/RANKL expression ratio in a dose- and time-dependent manner. In contrast, tumor necrosis factor-α (TNF-α) increased the expression of both OPG and RANKL in a time-dependent manner. The OPG/RANKL ratio was at a maximum two hours after TNF-α treatment and then returned to control levels. Furthermore, OPG was abundantly secreted into the media after transfection of OPG cDNA with Phi C31 integrase into 3T3L1 cells. Conclusion Our results indicate that OPG mRNA is expressed and regulated in the adipose tissue. Considering the role of OPG in obesity-associated inflammatory changes in adipose tissue and vessels, we speculate that OPG may have both a protective function against inflammation and anti-angiogenic effects on adipose tissue.

Ectopic expression of vasopressin V1b and V2 receptors in the adrenal glands of familial ACTH-independent macronodular adrenal hyperplasia

Objective  ACTH‐independent macronodular adrenal hyperplasia (AIMAH) is a rare and unusual cause of Cushings syndrome, characterized by bilateral nodular adrenocortical hyperplasia and hypersecretion of cortisol. Familial AIMAH has rarely been reported. Recently, the aberrant expression of adrenal receptors for various ligands in AIMAH patients has become important in explaining the pathogenesis of AIMAH. In this study, we present the cases of two sisters who were affected with AIMAH.

Impact of serum calcium and phosphate on coronary atherosclerosis detected by cardiac computed tomography

AIMS High calcium (Ca), phosphate (P), and Ca-P product (CPP) are associated with cardiovascular disease in patients with chronic kidney disease. Whether this relationship persists in individuals with normal kidney function is not yet elucidated. We explored the relationship of serum Ca, P, and CPP to coronary atherosclerosis assessed by cardiac computed tomography angiography (cCTA) in participants with normal kidney function. METHODS AND RESULTS This study included 7553 participants (52 ± 10 years, male 57%) with near-normal kidney function (estimated glomerular filtration rate > 60 mL/min/1.73 m2) who underwent cCTA. The relationship of Ca, P, and CPP to coronary atherosclerosis [coronary artery Ca score (CACS) >100 and the presence of coronary artery disease (CAD)] was evaluated. Higher Ca, P, and CPP were significantly associated with CACS > 100 continuously [adjusted odds ratio (OR) per mg/dL: Ca 1.21, P = 0.026; P 1.29, P < 0.001; CPP 1.03, P < 0.001]. However, they correlate only weakly with the presence of CAD (OR: Ca 1.17, P = 0.001; P 1.05, P = 0.173; CPP 1.01, P = 0.034). This discrepancy was because calcified or mixed plaque and non-calcified plaque (NCP) were included in CAD. A significant relationship was demonstrated between calcified or mixed plaque and Ca, P, and CPP (OR: Ca 1.20, P = 0.001; P 1.13, P = 0.003; CPP 1.02, P = 0.001), but not NCP. CONCLUSION Elevated serum levels of Ca, P, and CPP are significantly associated with the presence of calcified coronary atherosclerotic plaque. It is unclear if there is a causal relationship. This relationship is thought to contribute to vascular calcification, but is less closely associated with NCP.

Resorption Controls Bone Anabolism Driven by Parathyroid Hormone (PTH) Receptor Signaling in Osteocytes

Background: Contribution of resorption to bone anabolism by PTH receptor signaling in osteocytes is unknown. Results: Pharmacologic/genetic approaches demonstrated that remodeling- or modeling-based bone formation differentially operate in specific surfaces. Conclusion: Resorption is critical for anabolism in periosteal/endocortical bone surfaces, but tempers bone gain in cancellous bone. Significance: Targeting bone compartment-specific actions of PTH receptor signaling could enhance the therapeutic potential of the pathway. The contribution of remodeling-based bone formation coupled to osteoclast activity versus modeling-based bone formation that occurs independently of resorption, to the anabolic effect of PTH remains unclear. We addressed this question using transgenic mice with activated PTH receptor signaling in osteocytes that exhibit increased bone mass and remodeling, recognized skeletal effects of PTH elevation. Direct inhibition of bone formation was accomplished genetically by overexpressing the Wnt antagonist Sost/sclerostin; and resorption-dependent bone formation was inhibited pharmacologically with the bisphosphonate alendronate. We found that bone formation induced by osteocytic PTH receptor signaling on the periosteal surface depends on Wnt signaling but not on resorption. In contrast, bone formation on the endocortical surface results from a combination of Wnt-driven increased osteoblast number and resorption-dependent osteoblast activity. Moreover, elevated osteoclasts and intracortical/calvarial porosity is exacerbated by overexpressing Sost and reversed by blocking resorption. Furthermore, increased cancellous bone is abolished by Wnt inhibition but further increased by blocking resorption. Thus, resorption induced by PTH receptor signaling in osteocytes is critical for full anabolism in cortical bone, but tempers bone gain in cancellous bone. Dissecting underlying mechanisms of PTH receptor signaling would allow targeting actions in different bone compartments, enhancing the therapeutic potential of the pathway.

Expression and role of estrogen receptor α and β in medullary thyroid carcinoma: different roles in cancer growth and apoptosis

Medullary thyroid carcinoma (MTC) originates from parafollicular C cells. Estrogen receptorb (ERb) expression was detected in normal parafollicular C cells and MTC tumor tissue, but ERa expression in MTC tumors still remains undetermined. The appearance and loss of ERa or ERb expression has been known to play a role in the development and progression of many human cancers. We performed immunohistochemical studies of ERa ,E Rb, and Ki67, a mitotic index, in 11 human MTC tissue samples. ERa was detected in 10 cases (91%), and ERb expression was observed in 8 cases (72 . 7%). A majority (8/10) of ERa-positive tumors showing ERb Ki67 expression was detected in three cases (27 . 3%). Neither clinical parameters nor tumor node metastasis (TNM) tumor staging was correlated with the positivity for ERs or Ki67. To investigate the biological role of each ER, we used ER-negative MTC TT cells and adenoviral vectors carrying ERa (Ad-ERa), ERb (Ad-ERb), estrogen response element (ERE)-Luc (Ad-ERE-Luc), and activator protein 1 (AP1)-Luc (Ad-AP1-Luc). Estrogen stimulated and anti-estrogen, ICI 182 780, suppressed ERE reporter activity in TT cells expressing ERa or ERb ,s uggesting that both ERs use the same classical ERE-mediated pathway. Ad-ERa infection stimulated TT cell growth; in contrast, Ad-ERb infection suppressed their growth. Apoptosis was detected in Ad-ERb-infected TT cells. Estrogen and antiestrogen suppressed AP1 activity in Ad-ERa-infected cells, whereas upon Ad-ERb infection estrogen further stimulated AP1 activity which in turn is suppressed by anti-estrogen, suggesting that each ER acts differently through a non-EREmediated pathway. Our results suggest that ERa and ERb may play different roles in MTC tumor growth and progression.