Angiotensin AT4 ligands are potent, competitive inhibitors of insulin regulated aminopeptidase (IRAP)

Angiotensin IV (Ang IV) exerts profound effects on memory and learning, a phenomenon ascribed to its binding to a specific AT4 receptor. However the AT4 receptor has recently been identified as the insulin-regulated aminopeptidase (IRAP). In this study, we demonstrate that AT4 receptor ligands, including Ang IV, Nle1-Ang IV, divalinal-Ang IV, and the structurally unrelated LVV-hemorphin-7, are all potent inhibitors of IRAP catalytic activity, as assessed by cleavage of leu-β-naphthylamide by recombinant human IRAP. Both Ang IV and divalinal–Ang IV display competitive kinetics, indicating that AT4 ligands mediate their effects by binding to the catalytic site of IRAP. The AT4 ligands also displaced [125I]-Nle1-Ang IV or [125I]-divalinal1-Ang IV from IRAP-HEK293T membranes with high affinity, which was up to 200-fold greater than in the catalytic assay; this difference was not consistent among the peptides, and could not be ascribed to ligand degradation. Although some AT4 ligands were subject to minor cleavage by HEK293T membranes, none were substrates for IRAP. Of a range of peptides tested, only vasopressin, oxytocin, and met-enkephalin were rapidly cleaved by IRAP. We propose that the physiological effects of AT4 ligands result, in part, from inhibition of IRAP cleavage of neuropeptides involved in memory processing.

Endogenous parathyroid hormone is associated with reduced cartilage volume in vivo in a population-based sample of adult women

Objectives Animal and in vitro studies suggest that parathyroid hormone (PTH) may affect articular cartilage. However, little is known of the relationship between PTH and human joints in vivo.

Design Longitudinal.

Setting Barwon Statistical Division, Victoria, Australia.

Participants 101 asymptomatic women aged 35–49 years (2007–2009) and without clinical knee osteoarthritis, selected from the population-based Geelong Osteoporosis Study.

Risk factors Blood samples obtained 10 years before (1994–1997) and stored at −80°C for random batch analyses. Serum intact PTH was quantified by chemiluminescent enzyme assay. Serum 25-hydroxyvitamin D (25(OH)D) was assayed using equilibrium radioimmunoassay. Models were adjusted for age, bone area and body mass index; further adjustment was made for 25(OH)D and calcium supplementation.

Outcome Knee cartilage volume, measured by MRI.

Results A higher lnPTH was associated with reduced medial—but not lateral—cartilage volume (regression coefficient±SD, p value: −72.2±33.6 mm3, p=0.03) after adjustment for age, body mass index and bone area. Further sinusoidal adjustment (−80.8±34.4 mm3, p=0.02) and 25(OH)D with seasonal adjustment (−72.7±35.1 mm3, p=0.04), calcium supplementation and prevalent osteophytes did not affect the results.

Conclusions A higher lnPTH might be detrimental to knee cartilage in vivo. Animal studies suggest that higher PTH concentrations reduce the healing ability of cartilage following minor injury. This may be apparent in the presence of increased loading, which occurs in the medial compartment, placing the medial cartilage at higher risk for injury.

Does an increase in body mass index over 10 years affect knee structure in a population-based cohort study of adult women?

Introduction : Although obesity is a modifiable risk factor for knee osteoarthritis (OA), the effect of weight gain on knee structure in young and healthy adults has not been examined. The aim of this study was to examine the relationship between body mass index (BMI), and change in BMI over the preceding 10-year period, and knee structure (cartilage defects, cartilage volume and bone marrow lesions (BMLs)) in a population-based sample of young to middle-aged females.

Methods : One hundred and forty-two healthy, asymptomatic females (range 30 to 49 years) in the Barwon region of Australia, underwent magnetic resonance imaging (MRI) during 2006 to 2008. BMI measured 10 years prior (1994 to 1997), current BMI and change in BMI (accounting for baseline BMI) over this period, was assessed for an association with cartilage defects and volume, and BMLs.

Results : After adjusting for age and tibial plateau area, the risk of BMLs was associated with every increase in one-unit of baseline BMI (OR 1.14 (95% CI 1.03 to 1.26) P = 0.009), current BMI (OR 1.13 (95% CI 1.04 to 1.23) P = 0.005), and per one unit increase in BMI (OR 1.14 (95% CI 1.03 to 1.26) P = 0.01). There was a trend for a one-unit increase in current BMI to be associated with increased risk of cartilage defects (OR 1.06 (95% CI 1.00 to 1.13) P = 0.05), and a suggestion that a one-unit increase in BMI over 10 years may be associated with reduced cartilage volume (-17.8 ml (95% CI -39.4 to 3.9] P = 0.10). Results remained similar after excluding those with osteophytes.

Conclusions : This study provides longitudinal evidence for the importance of avoiding weight gain in women during early to middle adulthood as this is associated with increased risk of BMLs, and trend toward increased tibiofemoral cartilage defects. These changes have been shown to precede increased cartilage loss. Longitudinal studies will show whether avoiding weight gain in early adulthood may play an important role in diminishing the risk of knee OA.

Socioeconomic status and risk factors for obesity and metabolic disorders in a population-based sample of adult females

Objectives : The association between lower socioeconomic status (SES), obesity, lifestyle choices and adverse health consequences are well documented, however to date the relationship between these variables and area-based SES (equivalised for advantage and disadvantage) has not been examined simultaneously in one population or with more than tertiary divisions of SES. We set out to examine the risk factors for obesity and metabolic disorders in the same population across quintiles of area-based SES.

Methods : We performed a descriptive cross-sectional study using existing data from a population-based random selection of women aged 20–92 years (n = 1110) recruited from the Barwon Statistical Division, South Eastern Australia.

Results : All measures of adiposity were inversely associated with SES, and remained significant after adjusting for age. Lifestyle choices associated with adiposity and poorer health, including smoking, larger serving sizes of foods, and reduced physical activity, were significantly associated with individuals from lower SES groups.

Conclusions : Greater measures of adiposity and less healthy lifestyle choices were observed in individuals from lower SES. Significant differences in body composition were identified between quintiles 1 and 5, whereas subjects in the mid quintiles had relatively similar measures. The inverse relationship between SES, obesity and less healthy lifestyle underscores the possibility that these associations may be causal and should be investigated further.

Socioeconomic status, obesity and lifestyle in men : the Geelong Osteoporosis Study

Background : Although the association between lower socioeconomic status (SES) and obesity in women in developed countries is well-documented, current evidence regarding the relationship between obesity in men and area-based SES (equivalised for advantage and disadvantage) is inconsistent. Therefore, we aimed to examine obesity, lifestyle behaviours, physical activity in different domains and demographics in men using area-based SES.

Methods : We performed a descriptive cross-sectional study of 1467 randomly selected white men (mean age 56 year (inter-quartile range (IQR) = 39–73 year)) recruited from the Barwon Statistical Division, South Western Victoria, Australia between 2001–06.

Results : Age-adjusted BMI, waist circumference, % fat and lean mass and blood pressure were inversely associated with SES, with differences between low and upper SES (P for difference <0.05), independent of country of birth. Age-adjusted lifestyle behaviours associated with obesity and/or adverse health (especially cardiovascular disease), were also associated with lower SES.

Conclusions : Subjects from lower SES had greater measures of obesity despite being more physically active at work, but were less likely to be physically active in the domains of sports and/or leisure. These findings suggest the possible influence of lifestyle behaviours and occupation upon obesity in men and should be investigated further.

Socioeconomic status and bone mineral density in a population-based sample of men

Overall, socioeconomic status (SES) is inversely associated with poorer health outcomes. However, current literature provides conflicting data of the relationship between SES and bone mineral density (BMD) in men. In an age-stratified population-based randomly selected cross-sectional study of men (n = 1467) we assessed the association between SES and lifestyle exposures in relation to BMD. SES was determined by matching the residential address for each subject with Australian Bureau of Statistics 2006 census data for the study region. BMD was measured at the spine and femoral neck by dual energy X-ray absorptiometry. Lifestyle variables were collected by self-report. Regression models were age-stratified into younger and older groups and adjusted for age, weight, dietary calcium, physical activity, and medications known to affect bone. Subjects with spinal abnormalities were excluded from analyses of BMD at the spine. In younger men, BMD was highest at the spine in the mid quintiles of SES, where differences were observed compared to quintile 1 (1–7%, p < 0.05). In older men, the pattern of BMD across SES quintiles was reversed, and subjects from mid quintiles had the lowest BMD, with differences observed compared to quintile 5 (1–7%, p < 0.05). Differences in BMD at the spine across SES quintiles represent a potential 1.5-fold increase in fracture risk for those with the lowest BMD. There were no differences in BMD at the femoral neck. Further research is warranted which examines the mechanisms that may underpin differences in BMD across SES quintiles and to address the current paucity of data in this field of enquiry.

BMD in population-based adult women is associated with socioeconomic status

With few exceptions, an inverse relationship exists between social disadvantage and disease. However, there are conflicting data for the relationship between socioeconomic status (SES) and BMD. The aim of this study was to assess the association between SES and lifestyle exposures in relation to BMD. In a cross-sectional study conducted using 1494 randomly selected population-based adult women, we assessed the association between SES and lifestyle exposures in relation to BMD. BMD was measured at multiple anatomical sites by DXA. SES was determined by cross-referencing residential addresses with Australian Bureau of Statistics 1996 census data for the study region and categorized in quintiles. Lifestyle variables were collected by self-report. Regression models used to assess the relationship between SES and BMD were adjusted for age, height, weight, dietary calcium, smoking, alcohol consumption, physical activity, hormone therapy, and calcium/vitamin D supplements. Unadjusted BMD differed across SES quintiles (p < 0.05). At each skeletal site and SES index, a consistent peak in adjusted BMD was observed in the mid-quintiles. Differences in adjusted BMD were observed between SES quintiles 1 and 4 (3-7%) and between quintiles 5 and 4 (2-7%). At the spine, the maximum difference was observed (7.5%). In a subset of women, serum 25(OH)D explained a proportion of the association between SES and BMD (difference remained up to 4.2%). Observed differences in BMD across SES quintiles, consistent across both SES indices, suggest that low BMD may be evident for both the most disadvantaged and most advantaged.

The association between urban or rural locality and hip fracture in community-based adults : a systematic review

Urban or rural locality has been suggested to influence musculoskeletal health, with lower bone mineral density (BMD) and greater prevalence of fracture identified in urban residents. A computer-aided search of Medline, EMBASE, CINAHL and PsychINFO, January 1966 to November 2007 was conducted to identify studies investigating the relationship between urban or rural locality and the occurrence of hip fracture. The methodological quality of studies was assessed, and a best-evidence synthesis was used to summarise the results. Fourteen cohort studies and one case-control study were identified for inclusion in this review, indicating a lack of literature in the field. Best-evidence analysis identified moderate evidence for residents of rural regions to have lower risk of hip fracture compared to urban residents. Examining principal mechanisms for the observed relationship between urban/rural locality and hip fracture, such as factors at the person or area level, may help to identify modifiable risk factors and inform appropriate prevention strategies.

Behavioural and physical characteristics associated with vitamin D status in women

For most people in Australia, the primary source of vitamin D is casual exposure to sunlight. Hypovitaminosis D has been reported for high-risk populations, but little has been documented for women of all ages living in the community. Using cross-sectional data, we aimed to describe physical and behavioural characteristics associated with serum 25-hydroxyvitamin D (25OHD) for such women and to determine the association of serum 25OHD with hypertension and bone health. Serum 25OHD, parathyroid hormone (PTH), blood pressure, bone mineral density (BMD) and anthropometry were measured in a random sample of 861 women aged 20–92 years enrolled in the Geelong Osteoporosis Study, set in a temperate region at latitude 38–39°S. Lifestyle factors (including diet, smoking, medication use, socio-economic status, residence, education, occupation, and physical activity) were documented by questionnaire. In season-adjusted models for women aged 20–54 years, physical activity and living with a partner were independently and positively associated with serum 25OHD; associations with weight and waist–hip ratio were negative. Among older women, physical activity, vitamin D intake and urban dwelling were positively associated with serum 25OHD; age, weight and smoking were negative. Compared with the lowest tertile, those in the highest serum 25OHD tertile were less likely to have elevated serum PTH (adjusted OR = 0.25, 95% CI 0.16–0.41) and high blood pressure (adjusted OR = 0.40, 95% CI 0.22–0.72), and more likely to have normal hip and spine BMD (adjusted OR = 1.65, 95% CI 1.08–2.52). In multivariable models adjusting for season, age, weight (and height), BMD was associated with serum 25OHD at the spine, hip and whole body; no associations were detected at the forearm and no other characteristics were identified as confounders. Factors associated with high vitamin D status generally reflected healthy body habitus and active lifestyles. In contrast, excessive weight and smoking were associated with poorer vitamin D status. Women with high vitamin D were less likely to have elevated PTH, hypertension or bone deficits than women with poor levels.