Publications by authors named "Claes Ohlsson"

472 Publications

The "GEnomics of Musculo Skeletal Traits TranslatiOnal NEtwork": Origins, Rationale, Organization, and Prospects.

Front Endocrinol (Lausanne) 2021 16;12:709815. Epub 2021 Aug 16.

Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.

Musculoskeletal research has been enriched in the past ten years with a great wealth of new discoveries arising from genome wide association studies (GWAS). In addition to the novel factors identified by GWAS, the advent of whole-genome and whole-exome sequencing efforts in family based studies has also identified new genes and pathways. However, the function and the mechanisms by which such genes influence clinical traits remain largely unknown. There is imperative need to bring multidisciplinary expertise together that will allow translating these genomic discoveries into useful clinical applications with the potential of improving patient care. Therefore "GEnomics of MusculoSkeletal traits TranslatiOnal NEtwork" (GEMSTONE) aims to set the ground for the: 1) functional characterization of discovered genes and pathways; 2) understanding of the correspondence between molecular and clinical assessments; and 3) implementation of novel methodological approaches. This research network is funded by (COST). GEMSTONE includes six working groups (WG), each with specific objectives: WG1- creating, maintaining and updating an inventory of experts and resources (studies and datasets) participating in the network, helping to assemble focus groups defined by phenotype, functional and methodological expertise. WG2- describe ways to decompose the phenotypes of the different functional studies into meaningful components that will aid the interpretation of identified biological pathways. WG3 makes an inventory of genes underlying musculoskeletal monogenic conditions that aids the assignment of genes to GWAS signals and prioritizing GWAS genes as candidates responsible for monogenic presentations, through biological plausibility. WG4 : creating a roadmap of genes and pathways to be prioritized for functional assessment in cell and organism models of the musculoskeletal system. WG5 seeks the integration of the knowledge derived from the distinct efforts, with particular emphasis on systems biology and artificial intelligence applications. Finally, WG6 : makes a synopsis of the knowledge derived from the distinct efforts, allowing to prioritize factors within biological pathways, use refined disease trait definitions and/or improve study design of future investigations in a potential therapeutic context (e.g. clinical trials) for musculoskeletal diseases.
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http://dx.doi.org/10.3389/fendo.2021.709815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415473PMC
August 2021

Prevalence of overweight and obesity from 5 to 19 years of age in Gothenburg, Sweden.

Acta Paediatr 2021 Aug 31. Epub 2021 Aug 31.

Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Aim: The aim of this study was to present prevalence data for overweight and obesity across school age in a large, recent, population-based cohort of children in Gothenburg, Sweden.

Methods: We included 66,807 children (48.5% girls) aged 5-18.9 years who had their height and weight measured in school health care 2015-2018. The BMI values were categorised according to the age-dependent cut-offs for overweight and obesity from the International Obesity Task Force (IOTF).

Results: Overall, the prevalence of overweight and obesity for girls and boys was 18.1% and 18.0%, respectively. We observed increasing proportions of overweight (girls 11.5-17.1% and boys 8.4-17.4%) and obesity (girls 3.0-4.2% and boys 2.7-6.1%) with increasing age (p < 0.001 for trend in both sexes). Moreover, girls had higher prevalence of overweight during ages 5.0 to 8.9 years compared with boys (p < 0.001), while boys had higher prevalence of obesity 15.0-18.9 years compared with girls (p < 0.001).

Conclusion: In conclusion, we demonstrate increasing prevalence of overweight and obesity across the entire school age range, as well as differences in prevalences between boys and girls, in a population-based sample of 67,000 children in Gothenburg city, Sweden. Continuous monitoring of schoolchildren, together with effective preventive measures, is crucial to curb the obesity epidemic and its consequences.
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http://dx.doi.org/10.1111/apa.16089DOI Listing
August 2021

RSPO3 is important for trabecular bone and fracture risk in mice and humans.

Nat Commun 2021 08 13;12(1):4923. Epub 2021 Aug 13.

Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

With increasing age of the population, countries across the globe are facing a substantial increase in osteoporotic fractures. Genetic association signals for fractures have been reported at the RSPO3 locus, but the causal gene and the underlying mechanism are unknown. Here we show that the fracture reducing allele at the RSPO3 locus associate with increased RSPO3 expression both at the mRNA and protein levels, increased trabecular bone mineral density and reduced risk mainly of distal forearm fractures in humans. We also demonstrate that RSPO3 is expressed in osteoprogenitor cells and osteoblasts and that osteoblast-derived RSPO3 is the principal source of RSPO3 in bone and an important regulator of vertebral trabecular bone mass and bone strength in adult mice. Mechanistic studies revealed that RSPO3 in a cell-autonomous manner increases osteoblast proliferation and differentiation. In conclusion, RSPO3 regulates vertebral trabecular bone mass and bone strength in mice and fracture risk in humans.
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http://dx.doi.org/10.1038/s41467-021-25124-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363747PMC
August 2021

Testosterone reduces metabolic brown fat activity in male mice.

J Endocrinol 2021 Sep 3;251(1):83-96. Epub 2021 Sep 3.

Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Brown adipose tissue (BAT) burns substantial amounts of mainly lipids to produce heat. Some studies indicate that BAT activity and core body temperature are lower in males than females. Here we investigated the role of testosterone and its receptor (the androgen receptor; AR) in metabolic BAT activity in male mice. Castration, which renders mice testosterone deficient, slightly promoted the expression of thermogenic markers in BAT, decreased BAT lipid content, and increased basal lipolysis in isolated brown adipocytes. Further, castration increased the core body temperature. Triglyceride-derived fatty acid uptake, a proxy for metabolic BAT activity in vivo, was strongly increased in BAT from castrated mice (4.5-fold increase vs sham-castrated mice) and testosterone replacement reversed the castration-induced increase in metabolic BAT activity. BAT-specific AR deficiency did not mimic the castration effects in vivo and AR agonist treatment did not diminish the activity of cultured brown adipocytes in vitro, suggesting that androgens do not modulate BAT activity via a direct, AR-mediated pathway. In conclusion, testosterone is a negative regulator of metabolic BAT activity in male mice. Our findings provide new insight into the metabolic actions of testosterone.
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http://dx.doi.org/10.1530/JOE-20-0263DOI Listing
September 2021

Serum glycine levels are associated with cortical bone properties and fractures risk in men.

J Clin Endocrinol Metab 2021 Jul 23. Epub 2021 Jul 23.

Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

Context: In a recent study a pattern of 27 metabolites, including serum glycine, associated with bone mineral density (BMD).

Objective: To investigate associations for serum and urinary glycine levels with BMD, bone microstructure and fracture risk in men.

Methods: In the population based MrOS Sweden study (men, 69-81 years) serum glycine and BMD were measured at baseline (n=965) and 5-year follow up (n=546). Cortical and trabecular bone parameters of the distal tibia were measured at follow-up using high resolution peripheral quantitative computed tomography. Urinary (n=2,682) glycine was analyzed at baseline. X-ray validated fractures (n=594) were ascertained during a median follow-up of 9.6 years. Associations were evaluated using linear regression (bone parameters) or Cox regression (fractures).

Results: Circulating glycine levels were inversely associated with femoral neck (FN)-BMD. A meta-analysis (n=7,543) combining MrOS Sweden data with data from three other cohorts confirmed a robust inverse association between serum glycine levels and FN-BMD (p=7.7 x 10 -9). Serum glycine was inversely associated with the bone strength parameter failure load in the distal tibia (p=0.002), mainly as a consequence of an inverse association with cortical cross-sectional area and a direct association with cortical porosity. Both serum and urinary glycine levels predicted major osteoporotic fractures (serum, HR per SD increase = 1.20, 95% CI 1.03-1.40; urine HR=1.13, 95% CI 1.02-1.24). These fracture associations were only marginally reduced in models adjusted for FRAX with BMD.

Conclusions: Serum and urinary glycine are indirectly associated with FN-BMD and cortical bone strength, and directly associated with fracture risk in men.
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http://dx.doi.org/10.1210/clinem/dgab544DOI Listing
July 2021

The gravitostat protects diet-induced obese rats against fat accumulation and weight gain.

J Neuroendocrinol 2021 Aug 9;33(8):e12997. Epub 2021 Jul 9.

Department of Physiology/Endocrine, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

The gravitostat is a novel homeostatic body weight-regulating mechanism, mostly studied in mice, and recently confirmed in obese humans. In the present study, we explored the effect of weight loading on metabolic outcomes, meal patterns and parameters linked to energy expenditure in both obese and lean rats. Diet-induced obese (DIO) and lean rats were implanted with capsules weighing either 15% of biological body weight (load) or empty capsules (1.3% of body weight; controls). Loading protected against fat accumulation more markedly in the DIO group. In line with this, the obesity-related impairment in insulin sensitivity was notably ameliorated in DIO rats upon loading, as revealed by the reduction in serum insulin levels and homeostatic model assessment for insulin resistance index scores. Although 24-hour caloric intake was reduced in both groups, this effect was greater in loaded DIO rats than in loaded lean peers. During days 10-16, after recovery from surgery, loading: (i) decreased meal size in both groups (only during the light phase in DIO rats) but this was compensated in lean rats by an increase in meal frequency; (ii) reduced dark phase locomotor activity only in lean rats; and (iii) reduced mean caloric efficiency in DIO rats. Muscle weight was unaffected by loading in either group. Dietary-obese rats are therefore more responsive than lean rats to loading.
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http://dx.doi.org/10.1111/jne.12997DOI Listing
August 2021

Acute fat loss does not affect bone mass.

Sci Rep 2021 Jul 8;11(1):14177. Epub 2021 Jul 8.

Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Su Sahlgrenska, Vita Stråket 11, 413 45, Gothenburg, Sweden.

Obesity has previously been thought to protect bone since high body weight and body mass index are associated with high bone mass. However, some more recent studies suggest that increased adiposity negatively impacts bone mass. Here, we aimed to test whether acute loss of adipose tissue, via adipocyte apoptosis, alters bone mass in age-related obese mice. Adipocyte apoptosis was induced in obese male FAT-ATTAC mice through AP20187 dimerizer-mediated activation of caspase 8 selectively in adipocytes. In a short-term experiment, dimerizer was administered to 5.5 month-old mice that were terminated 2 weeks later. At termination, the total fat mass weighed 58% less in dimerizer-treated mice compared with vehicle-treated controls, but bone mass did not differ. To allow for the detection of long-term effects, we used 9-month-old mice that were terminated six weeks after dimerizer administration. In this experiment, the total fat mass weighed less (- 68%) in the dimerizer-treated mice than in the controls, yet neither bone mass nor biomechanical properties differed between groups. Our findings show that adipose tissue loss, despite the reduced mechanical loading, does not affect bone in age-related obese mice. Future studies are needed to test whether adipose tissue loss is beneficial during more severe obesity.
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http://dx.doi.org/10.1038/s41598-021-93450-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266894PMC
July 2021

Recent MMR vaccination in health care workers and Covid-19: A test negative case-control study.

Vaccine 2021 07 22;39(32):4414-4418. Epub 2021 Jun 22.

Dept. of Clinical Pharmacology, Sahlgrenska University Hospital, Gothenburg, Sweden; University of Gothenburg Vaccine Research Institute (GUVAX), Dept. of Microbiology and Immunology, Inst. of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. Electronic address:

Background: It has been hypothesised that the measles-mumps-rubella (MMR) vaccine may afford cross-protection against SARS-CoV-2 which may contribute to the wide variability in disease severity of Covid-19.

Methods: We employed a test negative case-control study, utilising a recent measles outbreak during which many healthcare workers received the MMR vaccine, to investigate the potential protective effect of MMR against SARS-CoV-2 in 5905 subjects (n = 805 males, n = 5100 females).

Results: The odds ratio for testing positive for SARS-CoV-2, in recently MMR-vaccinated compared to not recently MMR-vaccinated individuals was 0.91 (95% CI 0.76, 1.09). An interaction analysis showed a significant interaction for sex. After sex-stratification, the odds ratio for testing positive for males was 0.43 (95% CI 0.24, 0.79, P = 0.006), and 1.01 (95% CI 0.83, 1.22, P = 0.92) for females.

Conclusion: Our results indicate that there may be a protective effect of the MMR vaccine against SARS-CoV-2 in males but not females.
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http://dx.doi.org/10.1016/j.vaccine.2021.06.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216866PMC
July 2021

Low Birth Weight as an Early-Life Risk Factor for Adult Stroke Among Men.

J Pediatr 2021 Jun 27. Epub 2021 Jun 27.

Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Pediatric Clinical Research Center, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden. Electronic address:

Objective: To evaluate the association between birth weight and the risk of adult stroke in men, independent of body mass index (BMI) at young adult age.

Study Design: We included 35 659 men born between 1945 and 1961 from the BMI Epidemiology Study with data on birth weight together with BMI in childhood (8 years) and young adulthood (20 years). Information on stroke events (1184 first stroke events; 905 ischemic stroke [IS] events and 234 intracerebral hemorrhage [ICH] events) was retrieved from national registers in Sweden.

Results: Birth weight was inversely associated with the risk of stroke (IS, ICH and uncategorized together; hazard ratio [HR], 0.88 per SD increase, 95% CI, 0.84-0.93), IS, and ICH in a linear manner, independent of young adult BMI. This association was maintained when the analysis was restricted to individuals within the normal birth weight range only. Moreover, individuals with a birth weight in the lowest tertile followed by overweight at 20 years had an 81% greater risk of stroke (HR, 1.81; 95% CI, 1.29; 2.54), compared with a reference group of individuals with birth weight in the middle tertile who were of normal weight at age 20 years.

Conclusions: We demonstrate an inverse association between birth weight and the risk of adult stroke, IS, and ICH independent of young adult BMI. These findings suggest that low birth weight should be included in assessments of stroke risk in adults.
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http://dx.doi.org/10.1016/j.jpeds.2021.06.050DOI Listing
June 2021

What Cut-Point in Gait Speed Best Discriminates Community-Dwelling Older Adults With Mobility Complaints From Those Without? A Pooled Analysis From the Sarcopenia Definitions and Outcomes Consortium.

J Gerontol A Biol Sci Med Sci 2021 Sep;76(10):e321-e327

University of Florida, Gainesville, USA.

Background: Cut-points to define slow walking speed have largely been derived from expert opinion.

Methods: Study participants (13 589 men and 5043 women aged ≥65years) had walking speed (m/s) measured over 4-6 m (mean ± SD: 1.20 ± 0.27 m/s in men and 0.94 ± 0.24 m/s in women.) Mobility limitation was defined as any self-reported difficulty with walking approximately 1/4 mile (prevalence: 12.6% men, 26.4% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not.

Results: Among 5043 women, CART analysis identified 2 cut-points, classifying 4144 (82.2%) with walking speed ≥0.75 m/s, which we labeled as "fast"; 478 (9.5%) as "intermediate" (walking speed ≥0.62 m/s but <0.75 m/s); and 421 (8.3%) as "slow" (walking speed <0.62 m/s). Among 13 589 men, CART analysis identified 3 cut-points, classifying 10 001 (73.6%) with walking speed ≥1.00 m/s ("very fast"); 2901 (21.3%) as "fast" (walking speed ≥0.74 m/s but <1.00 m/s); 497 (3.7%) as "intermediate" (walking speed ≥0.57 m/s but <0.74 m/s); and 190 (1.4%) as "slow" (walking speed <0.57 m/s). Prevalence of self-reported mobility limitation was lowest in the "fast" or "very fast" (11% for men and 19% for women) and highest in the "slow" (60.5% in men and 71.0% in women). Rounding the 2 slower cut-points to 0.60 m/s and 0.75 m/s reclassified very few participants.

Conclusions: Cut-points in walking speed of approximately 0.60 m/s and 0.75 m/s discriminate those with self-reported mobility limitation from those without.
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http://dx.doi.org/10.1093/gerona/glab183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436986PMC
September 2021

Pubertal Body Mass Index Change Is Associated With Adult Coronary Atherosclerosis and Acute Coronary Events in Men.

Arterioscler Thromb Vasc Biol 2021 08 17;41(8):2318-2327. Epub 2021 Jun 17.

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Centre for Bone and Arthritis Research, the Sahlgrenska Academy at University of Gothenburg, Sweden (J.M.K., M.B., C.O.).

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.121.316265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288483PMC
August 2021

Physical exercise is associated with beneficial bone mineral density and body composition in young adults with childhood-onset inflammatory bowel disease.

Scand J Gastroenterol 2021 Jun 4;56(6):699-707. Epub 2021 May 4.

Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg and Queen Silvia's Children's Hospital, Gothenburg, Sweden.

Background: Patients with inflammatory bowel disease (IBD) have an increased risk of compromised bone mineral density (BMD) and body composition. There are limited data on the physical exercise (PE) habits of patients with childhood-onset IBD and on the associations between PE and BMD and body composition.

Patients And Methods: In total, 72 young adults with childhood-onset IBD and 1341 normative young adult controls answered questionnaires regarding PE [hours/week (h/w)] in the last 12 months. BMD and body composition were measured with dual x-ray absorptiometry (DXA) and presented as age- and gender-adjusted Z-scores for BMD, skeletal muscle index (SMI, the weight of lean mass in arms and legs/m), and percentage body fat (Fat %).

Results: A total of 41 (57%) patients with IBD engaged in PE during the previous 12 months, as compared to 913 (68%) of the controls ( = .053). Sedentary patients had significantly lower median BMD, SMI, and Fat % Z-scores than the controls with corresponding PE habits (all  < .05). In contrast, highly active (>4 h/week) patients had total body BMD, SMI, and Fat % in the same range as the controls with corresponding PE levels ( = .151,  = .992, and  = .189, respectively), albeit with lower BMDs in the spine ( = .007) and femoral neck ( = .015). Using multiple regression analyses, a diagnosis of childhood-onset IBD was independently associated with inferior BMD and body composition, regardless of the amount of PE.

Conclusion: Physical exercise is associated with beneficial bone mineral density and body composition in patients with IBD despite the negative effects of the disease.
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http://dx.doi.org/10.1080/00365521.2021.1913759DOI Listing
June 2021

Sarcopenia Definitions as Predictors of Fracture Risk Independent of FRAX , Falls, and BMD in the Osteoporotic Fractures in Men (MrOS) Study: A Meta-Analysis.

J Bone Miner Res 2021 07 8;36(7):1235-1244. Epub 2021 Apr 8.

Centre for Metabolic Bone Diseases, University of Sheffield, Sheffield, UK.

Dual-energy X-ray absorptiometry (DXA)-derived appendicular lean mass/height (ALM/ht ) is the most commonly used estimate of muscle mass in the assessment of sarcopenia, but its predictive value for fracture is substantially attenuated by femoral neck (fn) bone mineral density (BMD). We investigated predictive value of 11 sarcopenia definitions for incident fracture, independent of fnBMD, fracture risk assessment tool (FRAX ) probability, and prior falls, using an extension of Poisson regression in US, Sweden, and Hong Kong Osteoporois Fractures in Men Study (MrOS) cohorts. Definitions tested were those of Baumgartner and Delmonico (ALM/ht only), Morley, the International Working Group on Sarcopenia, European Working Group on Sarcopenia in Older People (EWGSOP1 and 2), Asian Working Group on Sarcopenia, Foundation for the National Institutes of Health (FNIH) 1 and 2 (using ALM/body mass index [BMI], incorporating muscle strength and/or physical performance measures plus ALM/ht ), and Sarcopenia Definitions and Outcomes Consortium (gait speed and grip strength). Associations were adjusted for age and time since baseline and reported as hazard ratio (HR) for first incident fracture, here major osteoporotic fracture (MOF; clinical vertebral, hip, distal forearm, proximal humerus). Further analyses adjusted additionally for FRAX-MOF probability (n = 7531; calculated ± fnBMD), prior falls (y/n), or fnBMD T-score. Results were synthesized by meta-analysis. In 5660 men in USA, 2764 Sweden and 1987 Hong Kong (mean ages 73.5, 75.4, and 72.4 years, respectively), sarcopenia prevalence ranged from 0.5% to 35%. Sarcopenia status, by all definitions except those of FNIH, was associated with incident MOF (HR = 1.39 to 2.07). Associations were robust to adjustment for prior falls or FRAX probability (without fnBMD); adjustment for fnBMD T-score attenuated associations. EWGSOP2 severe sarcopenia (incorporating chair stand time, gait speed, and grip strength plus ALM) was most predictive, albeit at low prevalence, and appeared only modestly influenced by inclusion of fnBMD. In conclusion, the predictive value for fracture of sarcopenia definitions based on ALM is reduced by adjustment for fnBMD but strengthened by additional inclusion of physical performance measures. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4293DOI Listing
July 2021

Inhibition of STAT3 prevents bone metastatic progression of prostate cancer in vivo.

Prostate 2021 Jun 6;81(8):452-462. Epub 2021 Apr 6.

Section for Oncology, Department of Radiation Sciences, Umeå University, Umeå, Sweden.

Background: Prostate cancer (PC) metastasizes to the skeleton forming predominantly sclerotic lesions, and there is currently no cure for bone metastatic disease. The transcription factor signal transducer and activator of transcription 3 (STAT3) is implicated as a metastatic driver, but its potential as therapeutic target in bone metastasis has not been investigated. In this study, we evaluated for the first time a STAT3 inhibitor, Napabucasin, as a therapeutic option for bone metastatic PC.

Methods: Effects of STAT3 inhibitors, Stattic and Napabucasin, on metastatic potential in PC cells were studied in vitro by assessment of migration capacity, self-renewal potential, and tumorsphere formation. For evaluation of the role of STAT3 in initial skeletal establishment of PC cells as well as in progressed castration-resistant PC (CRPC) in bone, human VCaP prostate cancer cells were inoculated in the tibia of mice which subsequently were treated with the STAT3 inhibitor Napabucasin. Bone specimens were analyzed using computed tomography (CT), immunohistochemistry, and quantitative polymerase chain reaction.

Results: The small molecule STAT3 inhibitors Stattic and Napabucasin both effectively impaired metastatic potential of PC cells in vitro. Furthermore, treatment with Napabucasin prevented metastatic establishment in tibial bones in vivo and thereby also the tumor-induced sclerotic bone response seen in vehicle-treated VCaP xenografts. In addition, treatment with Napabucasin of established bone CRPC significantly decreased both tumor burden and tumor-induced trabecular bone volume compared with effects seen in vehicle-treated animals. Anti-mitotic effects were confirmed by decreased Ki67 staining in Napabucasin-treated xenografts compared with vehicle-treated xenografts. Alterations of gene expression in the femoral bone marrow (BM) niche toward the maintenance of hematopoietic stem cells and the myeloid lineage were demonstrated by quantitative real-time polymerase chain reaction and were further reflected by a substantial increase in the number of erythrocytes in BM of Napabucasin-treated mice. Furthermore, a unique pattern of STAT3 phosphorylation in osteoblasts/stromal cells surrounding the areas of tumor cells was demonstrated immunohistochemically in bone xenograft models using several different PC cell lines.

Conclusion: Inhibition of STAT3 activity disrupts the bone metastatic niche and targets both the skeletal establishment of PC and advanced bone metastatic CRPC in mice, suggesting STAT3 as a candidate for molecular targeted therapies of skeletal metastatic disease.
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http://dx.doi.org/10.1002/pros.24125DOI Listing
June 2021

Osteocyte- and late osteoblast-derived NOTUM reduces cortical bone mass in mice.

Am J Physiol Endocrinol Metab 2021 05 22;320(5):E967-E975. Epub 2021 Mar 22.

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Osteoporosis is a common skeletal disease, with increased risk of fractures. Currently available osteoporosis treatments reduce the risk of vertebral fractures, mainly dependent on trabecular bone, whereas the effect on nonvertebral fractures, mainly dependent on cortical bone, is less pronounced. WNT signaling is a crucial regulator of bone homeostasis, and the activity of WNTs is inhibited by NOTUM, a secreted WNT lipase. We previously demonstrated that conditional inactivation of NOTUM in all osteoblast lineage cells increases the cortical but not the trabecular bone mass. The aim of the present study was to determine if NOTUM increasing cortical bone is derived from osteoblast precursors/early osteoblasts or from osteocytes/late osteoblasts. First, we demonstrated mRNA expression in expressing osteocytes and late osteoblasts in cortical bone using in situ hybridization. We then developed a mouse model with inactivation of NOTUM in -expressing osteocytes and late osteoblasts ( mice). We observed that the mice displayed a substantial reduction of mRNA in cortical bone, resulting in increased cortical bone mass and decreased cortical porosity in femur but no change in trabecular bone volume fraction in femur or in the lumbar vertebrae L5 in mice as compared with control mice. In conclusion, osteocytes and late osteoblasts are the principal source of NOTUM in cortical bone, and NOTUM derived from osteocytes/late osteoblasts reduces cortical bone mass. These findings demonstrate that inhibition of osteocyte/late osteoblast-derived NOTUM might be an interesting pharmacological target to increase cortical bone mass and reduce nonvertebral fracture risk. NOTUM produced by osteoblasts is known to regulate cortical bone mass. Our new findings show that NOTUM specifically derived by -expressing osteocytes and late osteoblasts regulates cortical bone mass and not trabecular bone mass.
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http://dx.doi.org/10.1152/ajpendo.00565.2020DOI Listing
May 2021

Association of Genetically Predicted Serum Estradiol With Risk of Thromboembolism in Men: A Mendelian Randomization Study.

J Clin Endocrinol Metab 2021 Jul;106(8):e3078-e3086

Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.

Context: An association was recently reported between genetic markers related to high testosterone and increased risk of thromboembolism in men, but a possible causal role of estradiol for risk of thromboembolism in men remains unknown.

Objective: This work aimed to determine whether endogenous estradiol has a causal role in thromboembolism in men.

Methods: A 2-sample mendelian randomization study using gene-based genetic instruments assessed the association between endogenous estradiol genetically predicted by 22 variants in the aromatase CYP19A1 gene region and the risk of thromboembolism (5815 cases) in 170 593 unrelated men of White ancestry in the UK Biobank. The main outcome measure included thromboembolism based on self-reports, hospital episodes, and death.

Results: Endogenous estradiol genetically predicted by variants in the CYP19A1 gene region was inversely associated with the risk of thromboembolism (odds ratio per SD increase in estradiol 0.74; 95% CI, 0.62-0.90). In contrast, genetic variants in the JMJD1C gene, used as a predictor of high endogenous testosterone, were associated with an increased risk of thromboembolism (odds ratio per SD increase in testosterone 1.39; 95% CI, 1.12-1.72). Subsequent explorative analyses evaluating potential repercussions of thromboembolism revealed that endogenous estradiol genetically predicted by variants in the CYP19A1 gene region was inversely associated with the risk of ischemic stroke (0.68; 95% CI, 0.49-0.95) but not myocardial infarction (0.97; 95% CI, 0.84-1.13).

Conclusion: Genetically predicted estradiol was inversely associated with the risk of thromboembolism and ischemic stroke in men. The ratio between testosterone and estradiol, determined by CYP19A1 activity, may contribute to the overall impact of sex steroids on thromboembolism in men.
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http://dx.doi.org/10.1210/clinem/dgab164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277207PMC
July 2021

A Body Weight Sensor Regulates Prepubertal Growth via the Somatotropic Axis in Male Rats.

Endocrinology 2021 Jun;162(6)

Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

In healthy conditions, prepubertal growth follows an individual specific growth channel. Growth hormone (GH) is undoubtedly the major regulator of growth. However, the homeostatic regulation to maintain the individual specific growth channel during growth is unclear. We recently hypothesized a body weight sensing homeostatic regulation of body weight during adulthood, the gravitostat. We now investigated if sensing of body weight also contributes to the strict homeostatic regulation to maintain the individual specific growth channel during prepubertal growth. To evaluate the effect of increased artificial loading on prepubertal growth, we implanted heavy (20% of body weight) or light (2% of the body weight) capsules into the abdomen of 26-day-old male rats. The body growth, as determined by change in biological body weight and growth of the long bones and the axial skeleton, was reduced in rats bearing a heavy load compared with light load. Removal of the increased load resulted in a catch-up growth and a normalization of body weight. Loading decreased hypothalamic growth hormone releasing hormone mRNA, liver insulin-like growth factor (IGF)-1 mRNA, and serum IGF-1, suggesting that the reduced body growth was caused by a negative feedback regulation on the somatotropic axis and this notion was supported by the fact that increased loading did not reduce body growth in GH-treated rats. Based on these data, we propose the gravitostat hypothesis for the regulation of prepubertal growth. This states that there is a homeostatic regulation to maintain the individual specific growth channel via body weight sensing, regulating the somatotropic axis and explaining catch-up growth.
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http://dx.doi.org/10.1210/endocr/bqab053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143665PMC
June 2021

Testosterone Reduces Body Fat in Male Mice by Stimulation of Physical Activity Via Extrahypothalamic ERα Signaling.

Endocrinology 2021 Jun;162(6)

Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven 3000, Belgium.

Testosterone (T) reduces male fat mass, but the underlying mechanisms remain elusive, limiting its clinical relevance in hypogonadism-associated obesity. Here, we subjected chemically castrated high-fat diet-induced adult obese male mice to supplementation with T or the nonaromatizable androgen dihydrotestosterone (DHT) for 20 weeks. Both hormones increased lean mass, thereby indirectly increasing oxygen consumption and energy expenditure. In addition, T but not DHT decreased fat mass and increased ambulatory activity, indicating a role for aromatization into estrogens. Investigation of the pattern of aromatase expression in various murine tissues revealed the absence of Cyp19a1 expression in adipose tissue while high levels were observed in brain and gonads. In obese hypogonadal male mice with extrahypothalamic neuronal estrogen receptor alpha deletion (N-ERαKO), T still increased lean mass but was unable to decrease fat mass. The stimulatory effect of T on ambulatory activity was also abolished in N-ERαKO males. In conclusion, our work demonstrates that the fat-burning action of T is dependent on aromatization into estrogens and is at least partially mediated by the stimulation of physical activity via extrahypothalamic ERα signaling. In contrast, the increase in lean mass upon T supplementation is mediated through the androgen receptor and indirectly leads to an increase in energy expenditure, which might also contribute to the fat-burning effects of T.
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http://dx.doi.org/10.1210/endocr/bqab045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140602PMC
June 2021

Opportunities and Challenges in Functional Genomics Research in Osteoporosis: Report From a Workshop Held by the Causes Working Group of the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society on October 5th 2020.

Front Endocrinol (Lausanne) 2020 15;11:630875. Epub 2021 Feb 15.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.

The discovery that sclerostin is the defective protein underlying the rare heritable bone mass disorder, sclerosteosis, ultimately led to development of anti-sclerostin antibodies as a new treatment for osteoporosis. In the era of large scale GWAS, many additional genetic signals associated with bone mass and related traits have since been reported. However, how best to interrogate these signals in order to identify the underlying gene responsible for these genetic associations, a prerequisite for identifying drug targets for further treatments, remains a challenge. The resources available for supporting functional genomics research continues to expand, exemplified by "multi-omics" database resources, with improved availability of datasets derived from bone tissues. These databases provide information about potential molecular mediators such as mRNA expression, protein expression, and DNA methylation levels, which can be interrogated to map genetic signals to specific genes based on identification of causal pathways between the genetic signal and the phenotype being studied. Functional evaluation of potential causative genes has been facilitated by characterization of the "osteocyte signature", by broad phenotyping of knockout mice with deletions of over 7,000 genes, in which more detailed skeletal phenotyping is currently being undertaken, and by development of zebrafish as a highly efficient additional model for functional studies of the skeleton. Looking to the future, this expanding repertoire of tools offers the hope of accurately defining the major genetic signals which contribute to osteoporosis. This may in turn lead to the identification of additional therapeutic targets, and ultimately new treatments for osteoporosis.
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http://dx.doi.org/10.3389/fendo.2020.630875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917291PMC
May 2021

Comparative Analysis of the Effects of Long-Term 3,5-diiodothyronine Treatment on the Murine Hepatic Proteome and Transcriptome Under Conditions of Normal Diet and High-Fat Diet.

Thyroid 2021 07 7;31(7):1135-1146. Epub 2021 Apr 7.

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Experimentelle Endokrinologie, Berlin, Germany.

The thyroid hormone (TH) metabolite 3,5-diiodothyronine (3,5-T2) is considered as a potential drug for treatment of nonalcoholic fatty liver disease (NAFLD) based on its prominent antisteatotic effects in murine models of obesity without the detrimental thyromimetic side effects known for classical TH. To expand our understanding of its mode of action, we comprehensively characterized the effects of 3,5-T2 on hepatic gene expression in a diet-induced murine model of obesity by a combined liver proteome and transcriptome analysis. Male C57BL/6 mice fed high-fat diet (HFD) to induce NAFLD or standard diet (SD) as control were treated with 2.5 μg/g body weight 3,5-T2 or saline for 4 weeks. We performed mass spectrometry analyses and integrated those proteome data with earlier published microarray-based transcriptome data from the same animals. In addition, concentrations of several sex steroids in serum and different tissues were determined by gas chromatography-tandem mass spectrometry. We observed limited concordance between transcripts and proteins exhibiting differential abundance under 3,5-T2 treatment, which was only partially explainable by methodological reasons and might, therefore, reflect noncanonical post-transcriptional events. The treatment affected the levels of more and partially different proteins under HFD as compared with SD, demonstrating response modulation by the hepatic lipid load. The hepatic physiological signatures of 3,5-T2 treatment inferable from the omics data comprised the reduction of oxidative stress and alteration of apolipoprotein profiles, both due to decreased liver fat content. In addition, induction of several classical TH target genes and genes involved in the biosynthesis of cholesterol, bile acids (BAs), and male sex steroids was observed. The latter finding was supported by hepatic sex steroid measurements. While confirming the beneficial hepatic liver fat reduction by 3,5-T2 treatment, our data suggest that besides the well-known induction of fatty acid oxidation the stimulation of cholesterol- and BA synthesis with subsequent excretion of the latter through bile might represent a further important mechanism in this context. The obvious intensified male sex steroid exposition of the liver in 3,5-T2-treated HFD animals can be predicted to cause enhanced hepatic "masculinization," with not yet clear but potentially detrimental physiological consequences.
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http://dx.doi.org/10.1089/thy.2020.0160DOI Listing
July 2021

Improved prediction of fracture risk leveraging a genome-wide polygenic risk score.

Genome Med 2021 02 3;13(1):16. Epub 2021 Feb 3.

Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Room H-413, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec, H3T 1E2, Canada.

Background: Accurately quantifying the risk of osteoporotic fracture is important for directing appropriate clinical interventions. While skeletal measures such as heel quantitative speed of sound (SOS) and dual-energy X-ray absorptiometry bone mineral density are able to predict the risk of osteoporotic fracture, the utility of such measurements is subject to the availability of equipment and human resources. Using data from 341,449 individuals of white British ancestry, we previously developed a genome-wide polygenic risk score (PRS), called gSOS, that captured 25.0% of the total variance in SOS. Here, we test whether gSOS can improve fracture risk prediction.

Methods: We examined the predictive power of gSOS in five genome-wide genotyped cohorts, including 90,172 individuals of European ancestry and 25,034 individuals of Asian ancestry. We calculated gSOS for each individual and tested for the association between gSOS and incident major osteoporotic fracture and hip fracture. We tested whether adding gSOS to the risk prediction models had added value over models using other commonly used clinical risk factors.

Results: A standard deviation decrease in gSOS was associated with an increased odds of incident major osteoporotic fracture in populations of European ancestry, with odds ratios ranging from 1.35 to 1.46 in four cohorts. It was also associated with a 1.26-fold (95% confidence interval (CI) 1.13-1.41) increased odds of incident major osteoporotic fracture in the Asian population. We demonstrated that gSOS was more predictive of incident major osteoporotic fracture (area under the receiver operating characteristic curve (AUROC) = 0.734; 95% CI 0.727-0.740) and incident hip fracture (AUROC = 0.798; 95% CI 0.791-0.805) than most traditional clinical risk factors, including prior fracture, use of corticosteroids, rheumatoid arthritis, and smoking. We also showed that adding gSOS to the Fracture Risk Assessment Tool (FRAX) could refine the risk prediction with a positive net reclassification index ranging from 0.024 to 0.072.

Conclusions: We generated and validated a PRS for SOS which was associated with the risk of fracture. This score was more strongly associated with the risk of fracture than many clinical risk factors and provided an improvement in risk prediction. gSOS should be explored as a tool to improve risk stratification to identify individuals at high risk of fracture.
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http://dx.doi.org/10.1186/s13073-021-00838-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860212PMC
February 2021

Mild stimulatory effect of a probiotic mix on bone mass when treatment is initiated 1.5 weeks after ovariectomy in mice.

Am J Physiol Endocrinol Metab 2021 03 1;320(3):E591-E597. Epub 2021 Feb 1.

Department of Internal Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Studies in humans and rodents show that probiotic bacteria can protect from bone loss caused by sex steroid deficiency. We showed earlier that a mixture of three probiotic bacteria, DSM13434, DSM 15312, and DSM 15313 ( mix), protects mice from ovariectomy (ovx)-induced bone loss when treatment was started 2 wk before sham and ovx surgery. In addition, the same probiotic treatment protected against lumbar spine bone loss in early postmenopausal women. In the present study, we wanted to evaluate the therapeutic potential of mix by starting treatment 1.5 wk after ovx when most of the rapid bone loss as a result of estrogen deficiency has already occurred. Treatment with mix for 5.5 wk increased the trabecular thickness but not the trabecular number in the proximal metaphyseal region of tibia compared with vehicle treatment. Cortical thickness and cortical area of the middiaphyseal part of the tibia were significantly decreased in ovx mice but not in . mix-treated ovx mice. The bone-protective effects of mix in ovx mice were associated with a protection against ovx-induced reduction of the frequency of regulatory T-cells and of the expression of in the bone marrow. In conclusion, the probiotic mix exerted a mild stimulatory effect on trabecular and cortical bone width when treatment is initiated 1.5 wk after ovariectomy in mice. This effect was associated with effects on bone-protecting regulatory T-cells. The results suggest that mix may exert beneficial effects on bone mass when treatment is started after ovariectomy. The probiotic mix exerted a mild stimulatory effect on trabecular and cortical bone width when treatment is initiated 1.5 wk after ovariectomy in mice. This effect was associated with effects on bone-protecting regulatory T-cells. The results suggest that mix may exert beneficial effects on bone mass when treatment is started after ovariectomy.
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http://dx.doi.org/10.1152/ajpendo.00412.2020DOI Listing
March 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 04;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Nat Commun 2021 01 28;12(1):654. Epub 2021 Jan 28.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10), arthritis (GDF5 p = 4 × 10), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
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http://dx.doi.org/10.1038/s41467-021-20918-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844411PMC
January 2021

Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease.

J Hum Genet 2021 Jun 20;66(6):625-636. Epub 2021 Jan 20.

Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.
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http://dx.doi.org/10.1038/s10038-020-00895-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144017PMC
June 2021

The influence of adult hip shape genetic variants on adolescent hip shape: Findings from a population-based DXA study.

Bone 2021 02 4;143:115792. Epub 2020 Dec 4.

Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Objective: Hip shape is a well-recognized risk factor for hip osteoarthritis (OA) and hip fracture. We aimed to investigate whether the genetic variants known to be associated with adult hip shape were also associated with adolescent hip shape.

Methods: Hip DXA scans, obtained in offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) at two time points (mean ages 13.8 and 17.8 years), were used to quantify hip morphology using a 53-point Statistical Shape Model (SSM). Principal component analysis was used to generate hip shape modes (HSMs). Genetic variants which had previously shown genome-wide significant association with specific HSMs in adults were tested for association with the same HSMs in adolescents (at each timepoint separately) using SNPTEST v2.

Results: Complete genotypic and phenotypic data were available for 3550 and 3175 individuals at 14 and 18 years, respectively. The strongest evidence for association with adolescent hip shape was for a variant located near SOX9 (rs2158915) with consistent effects across both time points for HSM1 (age 14: beta -0.05, p = 9.9 × 10; age 18: -0.05, p = 3.3 × 10) and HSM5 (age 14: beta -0.07, p = 1.6 × 10; age 18: -0.1, p = 2.7 × 10). There was also strong evidence of association between rs10743612 (near PTHLH) and HSM1 (age 14: 0.05, p = 1.1 × 10; age 18: 0.04, p = 0.003) and between rs6537291 (near HHIP) and HSM2 (age 14: -0.06, p = 0.001; age 18: -0.07, p = 0.001) across both time points. The genes with the strongest associations with hip shape in adolescents, (SOX9, PTHLH and HHIP) are known to be involved in endochondral bone formation. HSM1 indicates narrower aspect ratio of the upper femur, whereas both HSM2 and HSM5 reflect variation in the femoral head size and femoral neck width, features previously found to be related to the risk of OA in later life. The SOX9 locus has previously been found to associate with increased risk of hip fracture.

Conclusion: In conclusion, variants implicated in endochondral bone formation appear to consistently influence hip shape between adolescence and adulthood, including those aspects related to risk of hip OA and/or fracture in later life.
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http://dx.doi.org/10.1016/j.bone.2020.115792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809624PMC
February 2021

Low-level cadmium exposure is associated with decreased cortical thickness, cortical area and trabecular bone volume fraction in elderly men: The MrOS Sweden study.

Bone 2021 02 21;143:115768. Epub 2020 Nov 21.

Department of Geriatric Medicine, Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Centre for Bone and Arthritis Research (CBAR), Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

It is well known that high-level exposure to cadmium can cause bone disease such as osteoporosis, osteomalacia and fractures. However, the effect of low-level exposure, as found in the general population (mainly derived from diet and smoking), has only been assessed recently. The aim of this study was to examine if cadmium exposure in the general Swedish population causes other bone changes than decreased areal bone mineral density as measured by traditional DXA technology, e.g. changes in microstructure and geometry, such as cortical thickness or area, cortical porosity and trabecular bone volume. The study population consisted of 444 men, aged 70-81 years at inclusion year 2002-2004, from the Swedish cohort of the Osteoporotic Fractures in Men Study (MrOS). Cadmium was analyzed in baseline urine samples (U-Cd). Different parameters of bone geometry and microstructure were measured at the distal tibia at follow-up in 2009, including examination with high-resolution peripheral quantitative computed tomography (HR-pQCT). Associations between bone parameters and U-Cd in tertiles were estimated in multivariable analyses, including potential confounding factors (age, smoking, BMI, and physical activity). We found significant associations between U-Cd and several bone geometry or microstructure parameters, with 9% lower cortical thickness (p = 0.03), 7% lower cortical area (p = 0.04), and 5% lower trabecular bone volume fraction (p = 0.02) in the third tertile of U-Cd, using the first tertile as the reference. Furthermore, significant negative associations were found between log-transformed U-Cd and cortical thickness, cortical area, trabecular number and trabecular bone volume fraction, and a significant positive association with trabecular separation. The results indicate that low-level Cd exposure in the general population has negative effects on both cortical and trabecular bone.
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http://dx.doi.org/10.1016/j.bone.2020.115768DOI Listing
February 2021

Arginine site 264 in murine estrogen receptor-α is dispensable for the regulation of the skeleton.

Am J Physiol Endocrinol Metab 2021 01 23;320(1):E160-E168. Epub 2020 Nov 23.

Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Mutation of arginine 264 in ERα has been shown to abrogate rapid membrane ERα-mediated endothelial effects. Our novel finding that mutation of R264 is dispensable for ERα-mediated skeletal effects supports the concept that R264 determines tissue specificity of ERα. Estrogen protects against bone loss but is not a suitable treatment due to adverse effects in other tissues. Therefore, increased knowledge regarding estrogen signaling in estrogen-responsive tissues is warranted to aid the development of bone-specific estrogen treatments. Estrogen receptor-α (ERα), the main mediator of estrogenic effects in bone, is widely subjected to posttranslational modifications (PTMs). In vitro studies have shown that methylation at site R260 in the human ERα affects receptor localization and intracellular signaling. The corresponding amino acid R264 in murine ERα has been shown to have a functional role in endothelium in vivo, although the methylation of R264 in the murine gene is yet to be empirically demonstrated. The aim of this study was to investigate whether R264 in ERα is involved in the regulation of the skeleton in vivo. Dual-energy X-ray absorptiometry (DEXA) analysis at 3, 6, 9, and 12 mo of age showed no differences in total body areal bone mineral density (BMD) between R264A and wild type (WT) in either female or male mice. Furthermore, analyses using computed tomography (CT) demonstrated that trabecular bone mass in tibia and vertebra and cortical thickness in tibia were similar between R264A and WT mice. In addition, R264A females displayed a normal estrogen treatment response in trabecular bone mass as well as in cortical thickness. Furthermore, uterus, thymus, and adipose tissue responded similarly in R264A and WT female mice after estrogen treatment. In conclusion, our novel finding that mutation of R264 in ERα does not affect the regulation of the skeleton, together with the known role of R264 for ERα-mediated endothelial effects, supports the concept that R264 determines tissue specificity of ERα. Mutation of arginine 264 in ERα has been shown to abrogate rapid membrane ERα-mediated endothelial effects. Our novel finding that mutation of R264 is dispensable for ERα-mediated skeletal effects supports the concept that R264 determines tissue specificity of ERα.
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http://dx.doi.org/10.1152/ajpendo.00349.2019DOI Listing
January 2021

Revisiting the critical weight hypothesis for regulation of pubertal timing in boys.

Am J Clin Nutr 2020 Nov 12. Epub 2020 Nov 12.

Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Recent findings indicate that there is a body weight-sensing homeostatic regulation of body weight in postpubertal rodents and humans. It is possible that body weight sensing also might be involved in the regulation of pubertal timing. Although an early small study suggested that there is a critical body weight for pubertal timing in girls, most studies have focused on BMI and reported an inverse association between BMI and pubertal timing.

Objectives: In the present longitudinal well-powered cohort study, we revisited the critical weight hypothesis and tested if prepubertal body weight is a more robust inverse predictor of pubertal timing than prepubertal BMI in boys.

Method: We included men born during 1945-1961 (old cohort; n = 31,971) and men born during 1981-1996 (recent cohort; n = 1465) in the large BMI Epidemiology Study (BEST) Gothenburg (combined BEST cohort n = 33,436). Men with information on prepubertal body weight and BMI at 8 y of age and age at peak height velocity (PHV; an objective measure of pubertal timing) were included.

Results: Body weight explained more of the variance in age at PHV than BMI in both the old cohort and the recent cohort (combined cohort, body weight 6.3%, BMI 3.6%). Both body weight (β: -0.24 SD/SD increase in weight; 95% CI: -0.25, -0.23) and BMI (β: -0.18 SD/SD increase in BMI, 95% CI: -0.19, -0.17) were inversely associated with age at PHV but the association for body weight was significantly more pronounced than the association for BMI (P < 0.001).

Conclusions: In conclusion, prepubertal body weight is a more robust inverse predictor of pubertal timing than prepubertal BMI in boys. We propose that body weight sensing constitutes a feedback mechanism to regulate pubertal timing.
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http://dx.doi.org/10.1093/ajcn/nqaa304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779230PMC
November 2020

Increased estrogen to androgen ratio enhances immunoglobulin levels and impairs B cell function in male mice.

Sci Rep 2020 10 27;10(1):18334. Epub 2020 Oct 27.

Institute of Biomedicine, University of Turku, Turku, Finland.

Sex steroids, such as estrogens and androgens, are important regulators of the humoral immune response. Studies in female mice have demonstrated that alteration of circulating estrogen concentration regulates antibody-mediated immunity. As males have normally little endogenous estrogen, we hypothesized that in males high estrogens and low androgens affect the immune system and enhance the allergic inflammatory response. Here, we studied transgenic male mice expressing human aromatase (AROM+). These animals have a high circulating estrogen to androgen ratio (E/A), causing female traits such as gynecomastia. We found that AROM+ male mice had significantly higher plasma immunoglobulin levels, particularly IgE. Flow cytometry analyses of splenocytes revealed changes in mature/immature B cell ratio together with a transcriptional upregulation of the Igh locus. Furthermore, higher proliferation rate and increased IgE synthesis after IgE class-switching was found. Subsequently, we utilized an ovalbumin airway challenge model to test the allergic response in AROM+ male mice. In line with above observations, an increase in IgE levels was measured, albeit no impact on immune cell infiltration into the lungs was detected. Together, our findings suggest that high circulating E/A in males significantly alters B cell function without any significant enhancement in allergic inflammation.
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http://dx.doi.org/10.1038/s41598-020-75059-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591566PMC
October 2020
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