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  • 1. Baird, Denis A.
    et al.
    Evans, Daniel S.
    Kamanu, Frederick K.
    Gregory, Jennifer S.
    Saunders, Fiona R.
    Giuraniuc, Claudiu V.
    Barr, Rebecca J.
    Aspden, Richard M.
    Jenkins, Deborah
    Kiel, Douglas P.
    Orwoll, Eric S.
    Cummings, Steven R.
    Lane, Nancy E.
    Mullin, Benjamin H.
    Williams, Frances M.K.
    Richards, J. Brent
    Wilson, Scott G.
    Spector, Tim D.
    Faber, Benjamin G.
    Lawlor, Deborah A.
    Grundberg, Elin
    Ohlsson, Claes
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Capellini, Terence D
    Richard, Daniel
    Beck, Thomas J
    Evans, David M
    Paternoster, Lavinia
    Karasik, David
    Tobias, Jonathan H.
    Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies.2019In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 34, no 2, p. 241-251Article in journal (Refereed)
    Abstract [en]

    We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10-9 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2  > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

  • 2. Benetou, Vassiliki
    et al.
    Orfanos, Philippos
    Feskanich, Diane
    Michaëlsson, Karl
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Grodstein, Francine
    Wolk, Alicja
    Bellavia, Andrea
    Ahmed, Luai A
    Boffeta, Paolo
    Trichopoulou, Antonia
    Fruit and Vegetable Intake and Hip Fracture Incidence in Older Men and Women: The CHANCES Project2016In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 31, no 9, p. 1743-1752Article in journal (Refereed)
    Abstract [en]

    The role of fruit and vegetable intake in relation to fracture prevention during adulthood and beyond is not adequately understood. We investigated the potential association between fruit and vegetable intake and hip fracture incidence in a large sample of elderly from Europe and United States. A total of 142,018 individuals (among which 116,509 women), aged ≥60 years old, from five cohorts, were followed-up prospectively for 1,911,482 person-years accumulating 5,552 hip fractures. Fruit and vegetable intake was assessed by validated, cohort-specific, food-frequency questionnaires. Ηip fractures were ascertained through national patient registers or telephone interviews/questionnaires. Adjusted hazard ratios (HR) derived by Cox proportional-hazards regression were estimated for each cohort and subsequently pooled using random-effects meta-analysis. Intake of ≤ 1 servings/day of fruit and vegetables combined was associated with 39% higher hip fracture risk [pooled adjusted HR:1.39, 95% Confidence Intervals (CIs): 1.20, 1.58] in comparison to moderate intake (>3 and ≤5 servings/day) (pfor heterogeneity  = 0.505), whereas higher intakes (>5 servings/day) were not associated with lower risk in comparison to the same reference. Associations were more evident among women. We concluded that a daily intake of one or less servings of fruits and vegetables was associated with increased hip fracture risk in relation to moderate daily intakes. Older adults with such low fruit and vegetable consumption may benefit from raising their intakes to moderate amounts in order to reduce their hip fracture risk. 

  • 3.
    Bergman, Jonathan
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health. School of Sport Sciences, Arctic University of Norway, Tromsø, Norway.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Overestimation of the Limitations of Randomized Controlled Trials2019In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681Article in journal (Refereed)
  • 4. Johansson, Helena
    et al.
    Oden, Anders
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Jutberger, Hans
    Lorentzon, Mattias
    Barrett-Connor, Elizabeth
    Karlsson, Magnus K
    Ljunggren, Östen
    Smith, Ulf
    McCloskey, Eugene
    Kanis, John A
    Ohlsson, Claes
    Mellström, Dan
    High serum adiponectin predicts incident fractures in elderly men: osteoporotic fractures in men (MrOS) Sweden2012In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 27, no 6, p. 1390-1396Article in journal (Refereed)
    Abstract [en]

    Adipocytes and osteoblasts share a common progenitor, and there is, therefore, potential for both autocrine and endocrine effects of adiponectin on skeletal metabolism. The aim of the present study was to determine whether high serum adiponectin was associated with an increased risk of fracture in elderly men. We studied the relationship between serum adiponectin and the risk of fracture in 999 elderly men drawn from the general population and recruited to the Osteoporotic Fractures in Men (MrOS) study in Gothenburg, Sweden. Baseline data included general health questionnaires, lifestyle questionnaires, body mass index (BMI), bone mineral density (BMD), serum adiponectin, osteocalcin, and leptin. Men were followed for up to 7.4 years (average, 5.2 years). Poisson regression was used to investigate the relationship between serum adiponectin, other risk variables and the time-to-event hazard function of fracture. Median levels of serum adiponectin at baseline were 10.4 mu g/mL (interquartile range, 7.714.3). During follow-up, 150 men sustained one or more fractures. The risk of fracture increased in parallel with increasing serum adiponectin (hazard ratio [HR]/SD, 1.46; 95% confidence interval [CI], 1.231.72) and persisted after multivariate-adjusted analysis (HR/SD, 1.30; 95% CI, 1.091.55). Serum adiponectin shows graded stepwise association with a significant excess risk of fracture in elderly men that was independent of several other risk factors for fracture. Its measurement holds promise as a risk factor for fracture in men. (C) 2012 American Society for Bone and Mineral Research.

  • 5. Michaëlsson, Karl
    et al.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Garmo, Hans
    Byberg, Liisa
    Pedersen, Nancy L
    Melhus, Håkan
    Impact of hip fracture on mortality: a cohort study in hip fracture discordant identical twins2014In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 29, no 2, p. 424-431Article in journal (Refereed)
    Abstract [en]

    Several studies have shown a long-lasting higher mortality after hip fracture but the reasons of the excess risk is not well understood. We aimed to determine whether there exists a higher mortality after hip fracture when controlling for genetic constitution, shared environment, comorbidity and lifestyle by use of a nation-wide cohort study in hip fracture discordant monozygotic twins. All 286 identical Swedish twin pairs discordant for hip fracture (1972-2010) were identified. Comorbidity and lifestyle information was retrieved by registers and questionnaire information. We used intrapair Cox regression to compute multivariable-adjusted hazard ratios (HRs) for death. During follow-up, 143 twins with a hip fracture died (50%) compared to 101 twins (35%) without a hip fracture. Through the first year after hip fracture, the rate of death increased four-fold in women (HR 3.71; 95% confidence interval (CI) 1.32-10.40) and seven-fold in men (HR 6.67; 95% CI 1.47-30.13). The increased rate in women only persisted during the first year after hip fracture (HR after 1 year 0.99; 95% CI 0.66-1.50), whereas the corresponding HR in men was 2.58 (95% CI 1.02-6.62). The higher risk in men after the hip fracture event was successively attenuated during follow-up. After 5 years, the hazard ratio in men with a hip fracture was 1.19 (95% CI 0.29-4.90). On average, the hip fracture contributed to 0.9 years of life lost in women (95% CI 0.06-1.7) and 2.7 years in men (95% CI 1.7-3.7). The potential years of life lost associated with the hip fracture was especially pronounced in older men (>75 years), with an average loss of 47% (95% CI 31-61) of the expected remaining lifetime. We conclude that both women and men display a higher mortality after hip fracture independent of genes, comorbidity and lifestyle.

  • 6.
    Nordström, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Karlsson, Caroline
    Nyquist, Fredrik
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Karlsson, Magnus
    Bone loss and fracture risk after reduced physical activity.2005In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 20, no 2, p. 202-207Article in journal (Refereed)
    Abstract [en]

    Former male young athletes partially lost benefits in BMD (g/cm2) with cessation of exercise, but, despite this, had a higher BMD 4 years after cessation of career than a control group. A higher BMD might contribute to the lower incidence of fragility fractures found in former older athletes > or =60 years of age compared with a control group. INTRODUCTION: Physical activity increases peak bone mass and may prevent osteoporosis if a residual high BMD is retained into old age. MATERIALS AND METHODS: BMD was measured by DXA in 97 male young athletes 21.0 +/- 4.5 years of age (SD) and 48 controls 22.4 +/- 6.3 years of age, with measurements repeated 5 years later, when 55 of the athletes had retired from sports. In a second, older cohort, fracture incidence was recorded in 400 former older athletes and 800 controls > or =60 years of age. RESULTS: At baseline, the young athletes had higher BMD than controls in total body (mean difference, 0.08 g/cm2), spine (mean difference, 0.10 g/cm2), femoral neck (mean difference, 0.13 g/cm2), and arms (mean difference, 0.05 g/cm2; all p < 0.001). During the follow-up period, the young athletes who retired lost more BMD than the still active athletes at the femoral neck (mean difference, 0.07 g/cm2; p = 0.001) and gained less BMD at the total body (mean difference, 0.03 g/cm2; p = 0.004). Nevertheless, BMD was still higher in the retired young athletes (mean difference, 0.06-0.08 g/cm2) than in the controls in the total body, femoral neck, and arms (all p < 0.05). In the older cohort, there were fewer former athletes > or =60 of age than controls with fragility fractures (2.0% versus 4.2%; p < 0.05) and distal radius fractures (0.75% versus 2.5%; p < 0.05). CONCLUSIONS: Although exercise-induced BMD benefits are reduced after retirement from sports, former male older athletes have fewer fractures than matched controls.

  • 7.
    Nordström, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Olsson, Tommy
    Nordström, Peter
    Rapid loss of bone mineral density of the femoral neck after cessation of ice hockey training: a 6-year longitudinal study in males.2003In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 18, no 11, p. 1964-1969Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to evaluate the effect of training and reduced training on BMD in young ice hockey players during 6 years of follow-up. We found BMD gains in the femoral neck in the ice hockey group compared with controls. However, these gains were lost with reduced activity after cessation of career. INTRODUCTION: It has been suggested that increasing bone mass by intense physical activity during childhood and adolescence may decrease the risk of osteoporosis later in life. MATERIALS AND METHODS: In this longitudinal study, 43 ice hockey players (16.7 +/- 0.6 years) and 25 control subjects (16.8 +/- 0.3 years) were studied at baseline and after a mean period of 30 and 70 months. The groups did not differ in weight or height. Bone mineral density (BMD; g/cm2) was measured for total body, femoral neck, and spine using DXA. Volumetric BMD (vBMD; mg/cm3) of the femoral neck was estimated. RESULTS: The ice hockey players were found to have gained significantly more femoral neck BMD than controls (0.07 versus 0.03 g/cm2, p = 0.04) and to have gained femoral neck vBMD, whereas the controls did not (16 versus 0 mg/cm3, p = 0.049) between baseline and the first follow-up. At the first follow-up, the ice hockey players were found to have significantly higher BMD at the femoral neck and total body versus controls (p < 0.05). Between the first and second follow-ups, 21 ice hockey players stopped their active sports career. During this time period, these subjects lost significantly more femoral neck BMD (0.10 versus 0.02 g/cm2, p < 0.001) and femoral neck vBMD (38 versus 4 mg/cm3, p < 0.001) compared with the 22 ice hockey players who continued training. The former ice hockey players also lost significantly more neck vBMD (38 versus 14 mg/cm3, p = 0.009) compared with the controls during the same period. At the second follow-up, only the 22 ice hockey players who had continued their training were found to have significantly higher BMD at the femoral neck (p = 0.01), total body (p = 0.04), and spine (p = 0.02) compared with the controls. The former athletes were found to have intermediate BMD at all sites. CONCLUSION: In summary, we have demonstrated fast BMD loss at the femoral neck after decreased physical activity in young men. We conclude that ice hockey training during childhood and adolescence may not prevent the development of osteoporosis of the femoral neck later in life if the activity is not maintained.

  • 8.
    Nordström, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Franks, Paul
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Gustafson, Yngve
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Cognitive function in young men and the later risk of fractures2012In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 27, no 11, p. 2291-2297Article in journal (Refereed)
    Abstract [en]

    Dementia has been associated with an increased risk of fractures. These associations may be explained by an impaired cognitive function, as well as comorbid illness and toxic reaction from drugs. To investigate whether cognitive function in young, healthy individuals already affects the risk of fractures, overall cognitive function scores were calculated from four cognitive tests accomplished during a national conscriptions test in 960,956 men with a mean age of 18 years. Incident fractures were searched in national registers. During a median follow-up of 30 years (range 0 to 41 years), 65,313 men had one fracture and 2589 men had a hip fracture. Compared with men with no fracture, overall cognitive function at baseline was 3.5% lower for men sustaining one fracture and 5.5% lower for men sustaining a hip fracture (p < 0.001 for both). When comparing the lowest and the highest decile, low overall cognitive function scores increased the risk one fracture (hazard ratio [HR] = 1.55, 95% confidence interval [CI] 1.50-1.61) and a hip fracture (HR = 2.12, 95% CI 1.77-2.55), after adjustment for confounders. A higher education (university level versus elementary school) was associated with a decreased risk of a fracture (HR = 0.67, 95% CI 0.65-0.69) and a hip fracture (HR = 0.51, 95% CI 0.45-0.57). The effects of education and cognitive function were reduced when also adjusting for total income and disability pension. In summary, low cognitive function and education in young men were associated with the later risk of especially hip fractures. These associations may partly be mediated by socioeconomic factors. © 2012 American Society for Bone and Mineral Research.

  • 9.
    Nordström, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Type of physical activity, muscle strength, and pubertal stage as determinants of bone mineral density and bone area in adolescent boys.1998In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 13, no 7, p. 1141-8Article in journal (Refereed)
    Abstract [en]

    The present study was conducted to evaluate the influence of different types of weight-bearing physical activity, muscle strength, and puberty on bone mineral density (BMD, g/cm2) and bone area in adolescent boys. Three different groups were investigated. The first group consisted of 12 adolescent badminton players (age 17.0 +/- 0.8 years) training for 5.2 +/- 1.9 h/week. The second group consisted of 28 ice hockey players (age 16.9 +/- 0.3 years) training for 8.5 +/- 2.2 h/week. The third group consisted of 24 controls (age 16.8 +/- 0.3 years) training for 1.4 +/- 1.4h/week. The groups were matched for age, height, and pubertal stage. BMD, bone mineral content (BMC, g), and the bone area of the total body, lumbar spine, hip, femur and tibia diaphyses, distal femur, proximal tibia, and humerus were measured using dual-energy X-absorptiometry. When adjusting for the difference in body weight between the groups, the badminton players were found to have significantly higher BMD (p < 0.05) of the trochanter and distal femur compared with the ice hockey players despite a significantly lower weekly average training. The badminton players had higher BMD compared with the control with the control group at all weight-bearing BMD sites, except at the diaphyses of the femur and tibia and lumbar spine. The independent predictors of bone density were estimated by adjusting BMC for the bone area in a multivariate analysis among all subjects (n = 64). Accordingly, the bone density of all sites except the spine was significantly related to muscle strength and height, and the bone density of the total body, neck, trochanter, distal femur, and proximal tibia was significantly related to type of physical activity (beta = 0.09-0.33, p < 0.05). The bone area values at different sites were strongly related to muscle strength and height and less strongly related to the type of physical activity and pubertal stage. In conclusion, it seems that during late puberty in adolescent boys the type of weight-bearing physical activity is an important determinant of bone density, while the bone area is largely determined by parameters related to body size. The higher BMD at weight-bearing sites in badminton players compared with ice hockey players, despite significantly less average weekly training, indicates that physical activity including jumps in unusual directions has a great osteogenic potential.

  • 10.
    Nordström, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Sievänen, Harri
    Gustafson, Yngve
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Pedersen, Nancy L
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    High physical fitness in young adulthood reduces the risk of fractures later in life in men: a nationwide cohort study2013In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 28, no 5, p. 1061-1067Article in journal (Refereed)
    Abstract [en]

    A few studies indicate that self reported physical activity is associated with the risk of fractures in middle-aged and elderly men. We investigated whether objectively measured physical fitness in young adulthood was associated with the risk of low-energy fractures later in life in men. Aerobic capacity and isometric muscle strength were measured in 435445 Swedish men that conscripted for military service from 1969-1978. Incident fractures were searched in national registers. During a median follow-up period of 35 years (range, 11-41 years), 8 030 subjects sustained at least one fracture, increasing the risk of death 1.8 times (95% CI = 1.6-2.0) during follow up. When comparing men in the lowest and highest decile of physical fitness, the risk of a fracture was 1.8 times higher (95% CI = 1.6-2.1) and that of hip fracture was 2.7 times higher (95% CI = 1.6-4.7). The risk of fracture was also 1.4-1.5 times higher when comparing the extreme deciles of muscle strength (p < 0.001 for all). In a subcohort of 1009 twin pairs, up to 22% of the variation in physical fitness and 27-39% of the variation in muscle strength was attributable to environmental factors unique to one twin, e.g. physical activity. In conclusion, low aerobic capacity and muscle strength in young adulthood are associated with an increased risk of low-energy fractures later in life, while a low-energy fracture is associated with an increased risk of death already in middle-aged men.

  • 11.
    Pettersson, Ulrika
    et al.
    Bone research group, Institution of Medical Sciences, University of Aberdeen .
    Albagha, Omar M E
    Bone research group, Institution of Medical Sciences, University of Aberdeen .
    Mirolo, Max
    Institute of Biomedical technology, CNR, Via Fratelli Cervi, Milano, Italy.
    Taranta, Anna
    Department of Experimental Medicine, University of L'Aquila, Italy.
    Frattini, Annalisa
    Institute of Biomedical technology, CNR, Via Fratelli Cervi, Milano, Italy.
    McGuigan, Fiona E A
    Bone research group, Institution of Medical Sciences, University of Aberdeen .
    Vezzoni, Paolo
    Institute of Biomedical technology, CNR, Via Fratelli Cervi, Milano, Italy.
    Teti, Anna
    Institute of Biomedical technology, CNR, Via Fratelli Cervi, Milano, Italy.
    van Hul, Wim
    Department of Medical Genetics, University Hospital of Antwerp, Belgium.
    Reid, David M
    Bone research group, Institution of Medical Sciences, University of Aberdeen .
    Villa, Anna
    Ralston, Stuart H
    Bone research group, Institution of Medical Sciences, University of Aberdeen .
    Polymorphisms of the CLCN7 gene are associated with BMD in women.2005In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 20, no 11, p. 1960-7Article in journal (Refereed)
    Abstract [en]

    UNLABELLED: Here we show that a common polymorphism causing a valine to methionine amino acid substitution at codon 418 (V418M) in the CLCN7 gene is associated with femoral neck BMD in women. Our study adds to accumulating evidence that shows that common allelic variants in monogenic bone disease genes often contribute to BMD regulation in normal subjects.

    INTRODUCTION: The CLCN7 gene is a strong candidate for regulation of BMD, because mutations in CLCN7 cause some forms of osteopetrosis, a disease characterized by impaired osteoclast function and increased BMD. In this study, we sought to determine whether common allelic variation within CLCN7 was associated with BMD in the normal population.

    MATERIALS AND METHODS: We conducted mutation screening of the exons and intron-exon boundaries in CLCN7 by DNA sequencing in 50 normal subjects. We conducted an association study between common polymorphisms in CLCN7 and haplotypes defined by these polymorphisms and BMD values at the lumbar spine and femoral neck in a population-based cohort study of 1077 Scottish women 45-55 years of age.

    RESULTS: We identified 24 polymorphisms, but most were rare and only 4 had allele frequencies of >5%. These were a conservative single nucleotide polymorphism (SNP) in exon 1 (rs3751884), a 50-bp tandem repeat polymorphism within intron 8, and two SNPs within exon 15 (rs12926089 and rs12926669), of which one (rs12926669) predicts an amino acid change from valine to methionine at codon 418 (V418M). The exon 15 SNPs were in strong linkage disequilibrium and were both associated with femoral neck BMD (p = 0.001-0.003). None of the other polymorphisms were associated with BMD, and long-range haplotypes showed a much weaker association with BMD than the exon 15 SNPs. The V418M polymorphism was an independent predictor of femoral neck BMD on multiple regression analysis accounting for 1% of the variance in BMD at this site.

    CONCLUSIONS: Our study indicates that the V418M polymorphism of CLCN7 contributes to the genetic regulation of femoral neck BMD in women and adds to accumulating evidence that indicates that subtle polymorphic variation in genes that cause monogenic bone diseases also contribute to regulation of BMD in normal subjects.

  • 12. Sjögren, Klara
    et al.
    Engdahl, Cecilia
    Henning, Petra
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Tremaroli, Valentina
    Lagerquist, Marie K
    Backhed, Fredrik
    Ohlsson, Claes
    The gut microbiota regulates bone mass in mice2012In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 27, no 6, p. 1357-1367Article in journal (Refereed)
    Abstract [en]

    The gut microbiota modulates host metabolism and development of immune status. Here we show that the gut microbiota is also a major regulator of bone mass in mice. Germ-free (GF) mice exhibit increased bone mass associated with reduced number of osteoclasts per bone surface compared with conventionally raised (CONV-R) mice. Colonization of GF mice with a normal gut microbiota normalizes bone mass. Furthermore, GF mice have decreased frequency of CD4+ T cells and CD11b+/GR 1 osteoclast precursor cells in bone marrow, which could be normalized by colonization. GF mice exhibited reduced expression of inflammatory cytokines in bone and bone marrow compared with CONV-R mice. In summary, the gut microbiota regulates bone mass in mice, and we provide evidence for a mechanism involving altered immune status in bone and thereby affected osteoclast-mediated bone resorption. Further studies are required to evaluate the gut microbiota as a novel therapeutic target for osteoporosis. (C) 2012 American Society for Bone and Mineral Research.

  • 13. Smith, R
    et al.
    Ransjö, Maria
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Tatarczuch, L
    Song, SJ
    Pagel, C
    Morrison, JR
    Pike, RN
    Mackie, EJ
    Activation of protease-activated receptor-2 leads to inhibition of osteoclast differentiation.2004In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 19, no 3, p. 507-516Article in journal (Refereed)
    Abstract [en]

    PAR-2 is expressed by osteoblasts and activated by proteases present during inflammation. PAR-2 activation inhibited osteoclast differentiation induced by hormones and cytokines in mouse bone marrow cultures and may protect bone from uncontrolled resorption. INTRODUCTION: Protease-activated receptor-2 (PAR-2), which is expressed by osteoblasts, is activated specifically by a small number of proteases, including mast cell tryptase and factor Xa. PAR-2 is also activated by a peptide (RAP) that corresponds to the "tethered ligand" created by cleavage of the receptor's extracellular domain. The effect of activating PAR-2 on osteoclast differentiation was investigated. MATERIALS AND METHODS: Mouse bone marrow cultures have been used to investigate the effect of PAR-2 activation on osteoclast differentiation induced by parathyroid hormone (PTH), 1,25 dihydroxyvitamin D3 [1,25(OH)2D3], and interleukin-11 (IL-11). Expression of PAR-2 by mouse bone marrow, mouse bone marrow stromal cell-enriched cultures, and the RAW264.7 osteoclastogenic cell line was demonstrated by RT-PCR. RESULTS: RAP was shown to inhibit osteoclast differentiation induced by PTH, 1,25(OH)2D3, or IL-11. Semiquantitative RT-PCR was used to investigate expression of mediators of osteoclast differentiation induced by PTH, 1,25(OH)2D3, or IL-11 in mouse bone marrow cultures and primary calvarial osteoblast cultures treated simultaneously with RAP. In bone marrow and osteoblast cultures treated with PTH, 1,25(OH)2D3, or IL-11, RAP inhibited expression of RANKL and significantly suppressed the ratio of RANKL:osteoprotegerin expression. Activation of PAR-2 led to reduced expression of prostaglandin G/H synthase-2 in bone marrow cultures treated with PTH, 1,25(OH)2D3, or IL-11. RAP inhibited PTH- or 1,25(OH)2D3-induced expression of IL-6 in bone marrow cultures. RAP had no effect on osteoclast differentiation in RANKL-treated RAW264.7 cells. CONCLUSION: These observations indicate that PAR-2 activation inhibits osteoclast differentiation by acting on cells of the osteoblast lineage to modulate multiple mediators of the effects of PTH, 1,25(OH)2D3, and IL-11. Therefore, the role of PAR-2 in bone may be to protect it from uncontrolled resorption by limiting levels of osteoclast differentiation.

  • 14.
    Windahl, Sara H.
    et al.
    Department of Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Saxon, Leanne
    Borjesson, Anna E.
    Department of Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Lagerquist, Marie K.
    Department of Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Frenkel, Baruch
    Henning, Petra
    Department of Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Galea, Gabriel L.
    Meakin, Lee B.
    Engdahl, Cecilia
    Department of Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sjögren, Klara
    Department of Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Antal, Maria C.
    Krust, Andree
    Chambon, Pierre
    Lanyon, Lance E.
    Price, Joanna S.
    Ohlsson, Claes
    Department of Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Estrogen Receptor-alpha is required for the Osteogenic Response to mechanical loading in a Ligand-Independent manner involving its activation function 1 but Not 22013In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 28, no 2, p. 291-301Article in journal (Refereed)
    Abstract [en]

    Estrogen receptor-alpha (ER alpha) is crucial for the adaptive response of bone to loading but the role of endogenous estradiol (E2) for this response is unclear. To determine in vivo the ligand dependency and relative roles of different ERa domains for the osteogenic response to mechanical loading, gene-targeted mouse models with (1) a complete ERa inactivation (ER alpha(-/-)), (2) specific inactivation of activation function 1 (AF-1) in ER alpha (ER alpha AF-1(0)), or (3) specific inactivation of ER alpha AF-2 (ER alpha AF- 2(0)) were subjected to axial loading of tibia, in the presence or absence (ovariectomy [ovx]) of endogenous E2. Loading increased the cortical bone area in the tibia mainly as a result of an increased periosteal bone formation rate (BFR) and this osteogenic response was similar in gonadal intact and ovx mice, demonstrating that E2 (ligand) is not required for this response. Female ER alpha(-/-) mice displayed a severely reduced osteogenic response to loading with changes in cortical area (-78% +/- 15%, p < 0.01) and periosteal BFR (-81% +/- 9%, p < 0.01) being significantly lower than in wild-type (WT) mice. ER alpha AF-1(0) mice also displayed a reduced response to mechanical loading compared with WT mice (cortical area -40% +/- 11%, p < 0.05 and periosteal BFR -41% +/- 8%, p < 0.01), whereas the periosteal osteogenic response to loading was unaffected in ER alpha AF-2(0) mice. Mechanical loading of transgenic estrogen response element (ERE)-luciferase reporter mice did not increase luciferase expression in cortical bone, suggesting that the loading response does not involve classical genomic ERE-mediated pathways. In conclusion, ERa is required for the osteogenic response to mechanical loading in a ligand-independent manner involving AF-1 but not AF-2. (C) 2013 American Society for Bone and Mineral Research.

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