The calcium-sensing receptor (CaSR) is a G protein–coupled receptor (GPCR) that signals through Gq/11 and Gi/o to stimulate cytosolic calcium (Ca2+i) and mitogen-activated protein kinase (MAPK) signaling to control extracellular calcium homeostasis. Studies of loss- and gain-of-function CASR mutations, which cause familial hypocalciuric hypercalcemia type 1 (FHH1) and autosomal dominant hypocalcemia type 1 (ADH1), respectively, have revealed the CaSR to signal in a biased manner. Thus, some mutations associated with FHH1 lead to signaling predominantly through the MAPK pathway, whereas mutations associated with ADH1 preferentially enhance Ca2+i responses. Here, we report a previously unidentified ADH1-associated R680G CaSR mutation, which led to the identification of a CaSR structural motif that mediates biased signaling. Expressing the R680G CaSR mutant in HEK293 cells showed that this mutation increased MAPK signaling without altering Ca2+i responses. Moreover, this gain-of-function in MAPK activity occurred independently of Gq/11 and Gi/o, and was mediated instead by a non-canonical pathway involving β-arrestin scaffolding proteins. Homology modeling and mutagenesis studies showed the R680G CaSR mutation selectively enhanced β-arrestin signaling by disrupting a salt bridge formed between Arg680 and Glu767, which are located in the CaSR transmembrane domain 3 and extracellular loop-2, respectively. Thus, our results demonstrate CaSR signaling through β-arrestin and the importance of the Arg680-Glu767 salt bridge in mediating signaling bias.

Our objective was to assess whether administration of 25-OH-vitamin D to children with asthma treated with inhaled dry-powder budesonide 400 microg daily affects short-term growth or markers of bone turnover. We utilized a randomized, double-blind, two-period crossover trial with run-in and washout periods of 2 weeks and treatment periods of 4 weeks duration. The setting was an Outpatient clinic in a secondary referral center. Subjects included 14 boys and 3 girls with a mean age of 11.7 (range, 6.1-14.4) years. Interventions included 15 microg (600 IU) 25-OH-vitamin D (cholecalciferol) in one tablet ABCDin(R) once daily in the morning. Primary outcome measures were: lower leg growth rate, serum osteocalcin, and serum markers of type I collagen turnover, i.e., the amino terminal propeptide of type I procollagen (PINP), the carboxy terminal propeptide of type I procollagen (PICP) (formation markers), and the carboxy terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP) (degradation markers). Secondary outcome measures were parameters of asthma control and serum 25-OH-vitamin D. Lower leg growth rate was 0.22 mm/week during vitamin D and 0.25 mm/week during placebo treatment (NS). Osteocalcin was 59.9 and 57.8 microg/l during vitamin D and placebo treatment, respectively, PINP 574 and 565 microg/l, PICP 381 and 382 microg/l, and ICTP 11.5 and 11.1 microg/l, respectively (NS). Serum 25-OH-vitamin D was 76.3 nmol/l and 48.2 nmol/l, respectively (P < 0.001). There were no statistically significant differences in measures of pulmonary function. In conclusion, administration of 25-OH-vitamin D does not affect short-term growth or markers of bone turnover in children with asthma treated with inhaled dry-powder budesonide 400 microg daily.

BackgroundStudies indicate genetic and lifestyle factors can contribute to optimal bone development. In particular, the intensity level of physical activity may have an impact on bone health. This study aims to assess the relationship between physical activity at different intensities and Bone Mineral Content (BMC), Bone Mineral Density (BMD) and Bone Area (BA) accretion.MethodsThis longitudinal study is a part of The CHAMPS study-DK. Whole-body DXA scans were performed at baseline and after two years follows up. BMC, BMD, and BA were measured. The total body less head (TBLH) values were used. Physical activity (PA) was recorded by accelerometers (ActiGraph, model GT3X). Percentages of different PA intensity levels were calculated and log odds of two intensity levels of activity relative to the third level were calculated. Multilevel regression analyses were used to assess the relationship between the categories of physical activity and bone traits.ResultsOf 800 invited children, 742 (93%) accepted to participate. Of these, 682/742 (92%) participated at follow up. Complete datasets were obtained in 602/742 (81%) children. Mean (range) of age was 11.5 years (9.7-13.9). PA at different intensity levels was for boys and girls respectively, sedentary 62% and 64%, low 29% for both genders and moderate to high 9% and 7% of the total time. Mean (range) BMC, BMD, and BA was 1179 g (563–2326), 0.84 g/cm2 (0.64-1.15) and 1393 cm2 (851–2164), respectively. Valid accelerometer data were obtained for a mean of 6.1 days, 13 hours per day.ConclusionsThere 7was a positive relationship between the log odds of moderate to high-level PA versus low level activity and BMC, BMD and BA. Children with an increased proportion of time in moderate to high-level activity as opposed to sedentary and low-level activity achieved positive effects on BMC, BMD and BA.

Reductions in thickness of cutis and subcutis may account for some of the lower leg growth suppression caused by systemic glucocorticoids.

Background/Objective: Fracture risk is increased in patients with type 1 diabetes.We aimed to evaluate bone mineral density (BMD) and to identify risk factors associated to lower BMD in Danish children and adolescents with type 1 diabetes. Methods:In this cross-sectional study BMD Z-score were determined by dual-energy X-ray absorptiometry (DXA) from a cohort of otherwise healthy children and adolescents with type 1 diabetes. Puberty Tanner stage, hemoglobin A1c (HbA1c), disease duration, and age at diabetes onset were investigated for associations to DXA results. Results:We included 85 patients, 39 girls, 46 boys, with a median (range) age of 13.2 (6-17) years; disease duration 4.2 (0.4-15.9) years; HbA1c of the last year 61.8 (41-106) mmol/mol. Our patients were taller and heavier than the background population. When adjusted for increased height SD and body mass index SD, no overall difference in BMD Z-score was found. When stratified by sex, boys had significantly increased adjusted mean BMD Z-score, 0.38 (95% confidence interval [CI]: 0.13;0.62), girls; −0.27 (95% CI: −0.53;0.00). For the whole cohort, a negative correlation between mean latest year HbA1c and BMD Z-score was found, adjusted ß −0.019 (95%CI: −0.034;−0.004, P = 0.01). Poor glycemic control (HbA1c > 58 mmol/mol [7.5%]) within the latest year was likewise negatively correlated with BMD Z-score, adjusted ß −0.35 (95%CI: −0.69;−0.014, P = 0.04). Conclusions:Our study suggests that elevated blood glucose has a negative effect on the bones already before adulthood in patients with type 1 diabetes, although no signs of osteoporosis were identified by DXA. K E Y W O R D S adolescent, bone density, child, diabetes mellitusglycated hemoglobin A, type 1

Overweight, physical inactivity and sedentary behaviour have become increasing problems during the past decade. Increased sedentary behaviour may change the body composition (BC) by increasing the fat mass relative to the lean mass (LM). These changes may influence bone health to describe how anthropometry and BC predict the development of the bone accruement. The longitudinal study is a part of The CHAMPS study-DK. Children were DXA scanned at baseline and at 2-year follow-up. BC (LM, BF %) and BMC, BMD and BA were measured. The relationship between bone traits, anthropometry and BC was analysed by multilevel regression analyses. Of the invited children, 742/800 (93%) accepted to participate. Of these, 682/742 (92%) participated at follow-up. Mean (range) of age at baseline was 9.5 years (7.7-12.1). Height, BMI, LM and BF % predicted bone mineral accrual and bone size positively and independently. Height and BMI are both positive predictors of bone accruement. LM is a more precise predictor of bone traits than BF % in both genders. The effects of height and BMI and LM on bone accruement are nearly identical in the two genders, while changes in BF % have different but positive effects on bone accretion in both boys and girls.

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Short-term lower leg growth suppression induced by inhaled glucocorticoids is not confounded by variations in thickness of cutis or subcutis. The present observations further establishes knemometry as a reliable tool for assessment of the risk of growth suppression of inhaled glucocorticoids in children with asthma.