43 results on '"Grahnemo L"'
Search Results
2. Transplantation of gut microbiota from old mice into young healthy mice reduces lean mass but not bone mass
- Author
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Lawenius, L. (Lina), Cowardin, C. (Carrie), Grahnemo, L. (Louise), Scheffler, J. M. (Julia M.), Horkeby, K. (Karin), Engdahl, C. (Cecilia), Wu, J. (Jianyao), Vandenput, L. (Liesbeth), Koskela, A. (Antti), Tuukkanen, J. (Juha), Coward, E. (Eivind), Hveem, K. (Kristian), Langhammer, A. (Arnulf), Abrahamsson, S. (Sanna), Gordon, J. I. (Jeffrey I.), Sjögren, K. (Klara), Ohlsson, C. (Claes), Lawenius, L. (Lina), Cowardin, C. (Carrie), Grahnemo, L. (Louise), Scheffler, J. M. (Julia M.), Horkeby, K. (Karin), Engdahl, C. (Cecilia), Wu, J. (Jianyao), Vandenput, L. (Liesbeth), Koskela, A. (Antti), Tuukkanen, J. (Juha), Coward, E. (Eivind), Hveem, K. (Kristian), Langhammer, A. (Arnulf), Abrahamsson, S. (Sanna), Gordon, J. I. (Jeffrey I.), Sjögren, K. (Klara), and Ohlsson, C. (Claes)
- Abstract
Aging is associated with low bone and lean mass as well as alterations in the gut microbiota (GM). In this study, we determined whether the reduced bone mass and relative lean mass observed in old mice could be transferred to healthy young mice by GM transplantation (GMT). GM from old (21-month-old) and young adult (5-month-old) donors was used to colonize germ-free (GF) mice in three separate studies involving still growing 5- or 11-week-old recipients and 17-week-old recipients with minimal bone growth. The GM of the recipient mice was similar to that of the donors, demonstrating successful GMT. GM from old mice did not have statistically significant effects on bone mass or bone strength, but significantly reduced the lean mass percentage of still growing recipient mice when compared with recipients of GM from young adult mice. The levels of propionate in the cecum of mice receiving old donor GM were significantly lower than those in mice receiving young adult donor GM. Bacteroides ovatus was enriched in the microbiota of recipient mice harboring GM from young adult donors. The presence of B. ovatus was not only significantly associated with high lean mass percentage in mice, but also with lean mass adjusted for fat mass in the large human HUNT cohort. In conclusion, GM from old mice reduces lean mass percentage but not bone mass in young, healthy, still growing recipient mice. Future studies are warranted to determine whether GM from young mice improves the musculoskeletal phenotype of frail elderly recipient mice.
- Published
- 2023
3. Acute fat loss does not affect bone mass
- Author
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Lagerquist, M. K. (Marie K.), Gustafsson, K. L. (Karin L.), Henning, P. (Petra), Farman, H. (Helen), Wu, J. (Jianyao), Sjögren, K. (Klara), Koskela, A. (Antti), Tuukkanen, J. (Juha), Ohlsson, C. (Claes), Wernstedt Asterholm, I. (Ingrid), Grahnemo, L. (Louise), Lagerquist, M. K. (Marie K.), Gustafsson, K. L. (Karin L.), Henning, P. (Petra), Farman, H. (Helen), Wu, J. (Jianyao), Sjögren, K. (Klara), Koskela, A. (Antti), Tuukkanen, J. (Juha), Ohlsson, C. (Claes), Wernstedt Asterholm, I. (Ingrid), and Grahnemo, L. (Louise)
- Abstract
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.
- Published
- 2021
4. Associations entre les densités osseuses trabéculaires ou corticales et les calcifications coronaires : l’étude pilote SCAPIS
- Author
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Funck-Brentano, T., primary, Grahnemo, L., additional, Hjelmgren, O., additional, Brandberg, J., additional, Bergström, G., additional, and Ohlsson, C., additional
- Published
- 2020
- Full Text
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5. Glucose impairs B-1 cell function in diabetes
- Author
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Jennbacken, K., Ståhlman, S., Grahnemo, L., Wiklund, O., and Fogelstrand, L.
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- 2013
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6. Inter-relation between Interleukin (IL)-1, IL-6 and Body Fat Regulating Circuits of the Hypothalamic Arcuate Nucleus
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Schéle, E., Benrick, A., Grahnemo, L., Egecioglu, E., Anesten, F., Pálsdóttir, V., and Jansson, J.-O.
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- 2013
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7. Osteoporosis in a murine model of postmenopausal lupus
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Nordqvist, J, primary, Lagerquist, M K, additional, Grahnemo, L, additional, Koskela, A, additional, Islander, U, additional, and Carlsten, H, additional
- Published
- 2019
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8. Increased bone mass in a mouse model with low fat mass
- Author
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Grahnemo, L., primary, Gustafsson, K. L., additional, Sjögren, K., additional, Henning, P., additional, Lionikaite, V., additional, Koskela, A., additional, Tuukkanen, J., additional, Ohlsson, C., additional, Wernstedt Asterholm, I., additional, and Lagerquist, M. K., additional
- Published
- 2018
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9. Membrane estrogen receptor α is essential for estrogen signaling in the male skeleton
- Author
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Farman, H H, primary, Gustafsson, K L, additional, Henning, P, additional, Grahnemo, L, additional, Lionikaite, V, additional, Movérare-Skrtic, S, additional, Wu, J, additional, Ryberg, H, additional, Koskela, A, additional, Tuukkanen, J, additional, Levin, E R, additional, Ohlsson, C, additional, and Lagerquist, M K, additional
- Published
- 2018
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10. Osteoporosis in a murine model of postmenopausal lupus.
- Author
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Nordqvist, J, Lagerquist, M K, Grahnemo, L, Koskela, A, Islander, U, and Carlsten, H
- Subjects
SYSTEMIC lupus erythematosus ,BONE density ,OSTEOPOROSIS ,OSTEOPOROSIS in women ,CANCELLOUS bone - Abstract
Background/objective: Postmenopausal women with systemic lupus erythematosus have an increased risk of osteoporosis and associated fractures. Their increased osteoporosis risk is probably caused by a high level of inflammation, use of glucocorticoids, impaired kidney function, and early menopause as these are known risk factors for osteoporosis. Due to these risk factors and the lack of safe and effective treatments, new therapies for the treatment of osteoporosis in this group of patients are needed. Ovariectomized MRL/ lpr mice constitute a well-established model for studies of postmenopausal systemic lupus erythematosus; however, it is not clear to what extent this experimental model is associated with the development of osteoporosis. Thus, the aim of this study was to characterize the skeleton of ovariectomized MRL/ lpr mice to determine the suitability of this model in studies of prospective new therapies for osteoporosis in postmenopausal systemic lupus erythematosus patients. Methods: Skeletal parameters were measured in MRL/ lpr mice and MRL/++ control mice, using peripheral quantitative computed tomography, high-resolution micro-computed tomography and biomechanical analyses. mRNA expression of bone-remodeling markers was measured by quantitative polymerase chain reaction and serological markers of lupus disease were evaluated using ELISA. Results: Total bone mineral density was reduced in MRL/ lpr mice compared with MRL/++ mice and MRL/ lpr mice had reduced cortical and trabecular bone thickness compared with MRL/++ mice. In line with the low bone mass of MRL/ lpr mice, gene expression analysis of cortical bone from these mice indicated an increased osteoclast activity as well as a decreased osteoblastogenesis and osteoblast activity, compared with MRL/++ mice. Conclusion: Ovariectomized MRL/ lpr mice constitute a valuable experimental model for studies of osteoporosis development in postmenopausal systemic lupus erythematosus and this model is thus suitable for future studies of osteoporosis treatment in systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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11. Higher FSH Level Is Associated With Increased Risk Of Incident Hip Fracture In Older Adults, Independent Of Sex Hormones.
- Author
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Koh EH, Ewing SK, Sigurdsson S, Gudnason V, Hue TF, Vittinghoff E, Ohlsson C, Tivesten Å, Grahnemo L, Yuen T, Zaidi M, Rosen CJ, Schwartz AV, and Schafer AL
- Abstract
Context: Higher levels of FSH are associated with bone loss among women during the perimenopausal transition and among older men, independent of estradiol and testosterone levels, but whether higher FSH is an independent fracture risk factor is unknown., Objective: Determine whether baseline FSH level predicts subsequent hip fracture in older adults., Setting, Design, Participants: Using a case-cohort design, we randomly sampled 295 participants stratified by sex from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort, including 25 participants with incident hip fracture within 10 years after baseline. We sampled an additional 230 sex-stratified participants with incident hip fracture. Serum FSH and sex hormone levels were measured at baseline. Robust weighted Cox proportional hazards models were used to determine the relationship between FSH and hip fracture risk., Main Outcome: Incident hip fracture., Results: As no interaction was identified between FSH and sex for the relationship with fracture, men and women were pooled for analysis. Higher levels of FSH were associated with a significantly increased risk of incident hip fracture in models adjusted for age and sex [hazard ratio (HR) 1.24 (95% CI 1.04-1.48, p=0.02)] and after further adjustment for estradiol, testosterone, and sex hormone binding globulin levels [HR 1.20 (95% CI 1.01-1.44, p=0.04) per sex-specific SD increase in FSH level]., Conclusions: Higher FSH is associated with increased risk of subsequent hip fracture. Our findings support a growing body of evidence for direct pleiotropic effects of FSH on bone, and for a role for FSH in aging and disability independent of sex hormone levels., (Published by Oxford University Press on behalf of the Endocrine Society 2024.)
- Published
- 2024
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12. Associations of Serum Testosterone and Sex Hormone-Binding Globulin with Incident Fractures in Middle-Aged to Older Men.
- Author
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Grahnemo L, Marriott RJ, Murray K, Tyack LT, Nethander M, Matsumoto AM, Orwoll ES, Vanderschueren D, Yeap BB, and Ohlsson C
- Abstract
Context: As men age, circulating testosterone (T) decreases, circulating sex-hormone binding globulin (SHBG) increases, and risk of fracture increases. It is unclear if circulating T, independently of comorbidities, is associated with fracture risk in men., Objectives: To determine associations for T and SHBG with incident fractures in men., Methods: We utilized the large (n=205,973 participants, 11,088 any fracture cases, 1,680 hip fracture cases, 1,366 forearm fracture cases) and well-characterized UK Biobank cohort. Associations were modelled using Cox regressions, adjusting for multiple comorbidities/covariates, imputing for missing information, and assessing non-linearity using cubic splines., Results: For T, not considering SHBG, there was a non-linear association with hip but not forearm fractures, with the lowest risk in the second quintile. However, in models adjusted for SHBG or using calculated free T, lower T was associated with higher risk for fractures at all evaluated bone sites. Lower SHBG was strongly associated with lower risk of hip and forearm fractures (Q1 vs Q5, hip 0.55, 0.47-0.65; forearm 0.62, 0.52-0.74)., Conclusion: Low circulating SHBG is strongly associated with low risk of fracture at all evaluated bone sites, while the associations of circulating T with fracture risk are of lesser magnitude, non-linear, inconsistent among fracture site, and affected by adjustment for SHBG. These findings demonstrate that circulating SHBG, rather than T, is a major independent biomarker of fracture risk in men. Consequently, both total T and SHBG should be assessed when examining the relationship of endogenous T concentrations with fractures in middle-aged to older men., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)
- Published
- 2024
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13. Publisher Correction: A plasma protein-based risk score to predict hip fractures.
- Author
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Austin TR, Nethander M, Fink HA, Törnqvist AE, Jalal DI, Buzkova P, Barzilay JI, Carbone L, Gabrielsen ME, Grahnemo L, Lu T, Hveem K, Jonasson C, Kizer JR, Langhammer A, Mukamal KJ, Gerszten RE, Psaty BM, Robbins JA, Sun YV, Skogholt AH, Kanis JA, Johansson H, Åsvold BO, Valderrabano RJ, Zheng J, Richards JB, Coward E, and Ohlsson C
- Published
- 2024
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14. Associations between gut microbiota and incident fractures in the FINRISK cohort.
- Author
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Grahnemo L, Kambur O, Lahti L, Jousilahti P, Niiranen T, Knight R, Salomaa V, Havulinna AS, and Ohlsson C
- Subjects
- Humans, Male, Female, Middle Aged, Finland epidemiology, Aged, Bacteria classification, Bacteria genetics, Bacteria isolation & purification, Metagenome, Cohort Studies, Incidence, Metagenomics methods, Proteobacteria genetics, Proteobacteria isolation & purification, Risk Factors, Adult, Gastrointestinal Microbiome, Fractures, Bone microbiology, Fractures, Bone epidemiology, Fractures, Bone etiology
- Abstract
The gut microbiota (GM) can regulate bone mass, but its association with incident fractures is unknown. We used Cox regression models to determine whether the GM composition is associated with incident fractures in the large FINRISK 2002 cohort (n = 7043, 1092 incident fracture cases, median follow-up time 18 years) with information on GM composition and functionality from shotgun metagenome sequencing. Higher alpha diversity was associated with decreased fracture risk (hazard ratio [HR] 0.92 per standard deviation increase in Shannon index, 95% confidence interval 0.87-0.96). For beta diversity, the first principal component was associated with fracture risk (Aitchison distance, HR 0.90, 0.85-0.96). In predefined phyla analyses, we observed that the relative abundance of Proteobacteria was associated with increased fracture risk (HR 1.14, 1.07-1.20), while the relative abundance of Tenericutes was associated with decreased fracture risk (HR 0.90, 0.85-0.96). Explorative sub-analyses within the Proteobacteria phylum showed that higher relative abundance of Gammaproteobacteria was associated with increased fracture risk. Functionality analyses showed that pathways related to amino acid metabolism and lipopolysaccharide biosynthesis associated with fracture risk. The relative abundance of Proteobacteria correlated with pathways for amino acid metabolism, while the relative abundance of Tenericutes correlated with pathways for butyrate synthesis. In conclusion, the overall GM composition was associated with incident fractures. The relative abundance of Proteobacteria, especially Gammaproteobacteria, was associated with increased fracture risk, while the relative abundance of Tenericutes was associated with decreased fracture risk. Functionality analyses demonstrated that pathways known to regulate bone health may underlie these associations., (© 2024. The Author(s).)
- Published
- 2024
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15. A plasma protein-based risk score to predict hip fractures.
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Austin TR, Nethander M, Fink HA, Törnqvist AE, Jalal DI, Buzkova P, Barzilay JI, Carbone L, Gabrielsen ME, Grahnemo L, Lu T, Hveem K, Jonasson C, Kizer JR, Langhammer A, Mukamal KJ, Gerszten RE, Psaty BM, Robbins JA, Sun YV, Skogholt AH, Kanis JA, Johansson H, Åsvold BO, Valderrabano RJ, Zheng J, Richards JB, Coward E, and Ohlsson C
- Subjects
- Humans, Female, Male, Risk Assessment methods, Aged, Risk Factors, Middle Aged, Bone Density, Hip Fractures blood, Hip Fractures epidemiology, Proteomics methods, Blood Proteins metabolism, Blood Proteins analysis
- Abstract
As there are effective treatments to reduce hip fractures, identification of patients at high risk of hip fracture is important to inform efficient intervention strategies. To obtain a new tool for hip fracture prediction, we developed a protein-based risk score in the Cardiovascular Health Study using an aptamer-based proteomic platform. The proteomic risk score predicted incident hip fractures and improved hip fracture discrimination in two Trøndelag Health Study validation cohorts using the same aptamer-based platform. When transferred to an antibody-based proteomic platform in a UK Biobank validation cohort, the proteomic risk score was strongly associated with hip fractures (hazard ratio per s.d. increase, 1.64; 95% confidence interval 1.53-1.77). The proteomic risk score, but not available polygenic risk scores for fractures or bone mineral density, improved the C-index beyond the fracture risk assessment tool (FRAX), which integrates information from clinical risk factors (C-index, FRAX 0.735 versus FRAX + proteomic risk score 0.776). The developed proteomic risk score constitutes a new tool for stratifying patients according to hip fracture risk; however, its improvement in hip fracture discrimination is modest and its clinical utility beyond FRAX with information on femoral neck bone mineral density remains to be determined., (© 2024. The Author(s).)
- Published
- 2024
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16. Optic disc drusen: Dystrophic calcification, a potential target for treatment.
- Author
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Bentin JM, Heegaard S, Jørgensen NR, Grahnemo L, and Hamann S
- Subjects
- Humans, Visual Acuity physiology, Optic Disk Drusen diagnosis, Calcinosis
- Abstract
Optic disc drusen (ODD) are calcified, acellular bodies, seen in the optic nerve head of up to 2% of the population. Although seldomly affecting visual acuity, visual field defects are common, and severe, ischemic complications causing irreversible vision loss are known to occur. Different treatment strategies for ODD have been explored, but so far without success. This review focuses on the unique, calcified property of ODD, describing what we know about ODD pathogenesis and previously tried treatment strategies. In this context, we discuss current knowledge about calcium and pathological calcifications, including intracranial and ocular calcifications. We also explore some of the obstacles that must be addressed to develop a therapy centred on the concept of calcification, should calcification be identified as a pathogenic factor contributing to vision loss., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)
- Published
- 2024
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17. Large-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures.
- Author
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Austin TR, Fink HA, Jalal DI, Törnqvist AE, Buzkova P, Barzilay JI, Lu T, Carbone L, Gabrielsen ME, Grahnemo L, Hveem K, Jonasson C, Kizer JR, Langhammer A, Mukamal KJ, Gerszten RE, Nethander M, Psaty BM, Robbins JA, Sun YV, Skogholt AH, Åsvold BO, Valderrabano RJ, Zheng J, Richards JB, Coward E, and Ohlsson C
- Subjects
- Humans, Female, Male, Incidence, Aged, Blood Proteins metabolism, Risk Factors, Hip Fractures blood, Hip Fractures epidemiology, Proteome metabolism
- Abstract
Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. In an exploratory search of the underlying biology as reflected through the circulating proteome, we performed a comprehensive Circulating Proteome Association Study (CPAS) meta-analysis for incident hip fractures. Analyses included 6430 subjects from two prospective cohort studies (Cardiovascular Health Study and Trøndelag Health Study) with circulating proteomics data (aptamer-based 5 K SomaScan version 4.0 assay; 4979 aptamers). Associations between circulating protein levels and incident hip fractures were estimated for each cohort using age and sex-adjusted Cox regression models. Participants experienced 643 incident hip fractures. Compared with the individual studies, inverse-variance weighted meta-analyses yielded more statistically significant associations, identifying 23 aptamers associated with incident hip fractures (conservative Bonferroni correction 0.05/4979, P < 1.0 × 10-5). The aptamers most strongly associated with hip fracture risk corresponded to two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR. High levels of several inflammation-related proteins (CD14, CXCL12, MMP12, ITIH3) were also associated with increased hip fracture risk. Ingenuity pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. These analyses identified several circulating proteins and pathways consistently associated with incident hip fractures. These findings underscore the usefulness of the meta-analytic approach for comprehensive CPAS in a similar manner as has previously been observed for large-scale human genetic studies. Future studies should investigate the underlying biology of these potential novel drug targets., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)
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- 2024
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18. An atlas of genetic determinants of forearm fracture.
- Author
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Nethander M, Movérare-Skrtic S, Kämpe A, Coward E, Reimann E, Grahnemo L, Borbély É, Helyes Z, Funck-Brentano T, Cohen-Solal M, Tuukkanen J, Koskela A, Wu J, Li L, Lu T, Gabrielsen ME, Mägi R, Hoff M, Lerner UH, Henning P, Ullum H, Erikstrup C, Brunak S, Langhammer A, Tuomi T, Oddsson A, Stefansson K, Pettersson-Kymmer U, Ostrowski SR, Pedersen OBV, Styrkarsdottir U, Mäkitie O, Hveem K, Richards JB, and Ohlsson C
- Subjects
- Animals, Mice, Genome-Wide Association Study, Bone Density genetics, Risk Factors, Forearm, Fractures, Bone genetics
- Abstract
Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4
-/- mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures., (© 2023. The Author(s).)- Published
- 2023
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19. Low Circulating Valine Associate With High Risk of Hip Fractures.
- Author
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Grahnemo L, Eriksson AL, Nethander M, Johansson R, Lorentzon M, Mellström D, Pettersson-Kymmer U, and Ohlsson C
- Subjects
- Male, Humans, Valine, Bone Density, Cortical Bone, Risk Factors, Hip Fractures epidemiology, Hip Fractures etiology, Osteoporotic Fractures epidemiology, Osteoporotic Fractures etiology
- Abstract
Context: Hip fractures constitute a major health concern. An adequate supply of amino acids is crucial to ensure optimal acquisition and remodeling of bone. Circulating amino acid levels have been proposed as markers of bone mineral density, but data on their ability to predict incident fractures are scarce., Objectives: To investigate the associations between circulating amino acids and incident fractures., Methods: We used UK Biobank (n = 111 257; 901 hip fracture cases) as a discovery cohort and the Umeå Fracture and Osteoporosis (UFO) hip fracture study (hip fracture cases n = 2225; controls n = 2225) for replication. Associations with bone microstructure parameters were tested in a subsample of Osteoporotic Fractures in Men Sweden (n = 449)., Results: Circulating valine was robustly associated with hip fractures in the UK Biobank (HR per SD increase 0.79, 95% CI 0.73-0.84), and this finding was replicated in the UFO study (combined meta-analysis including 3126 incident hip fracture cases, odds ratio per SD increase 0.84, 95% CI 0.80-0.88). Detailed bone microstructure analyses showed that high circulating valine was associated with high cortical bone area and trabecular thickness., Conclusion: Low circulating valine is a robust predictor of incident hip fractures. We propose that circulating valine may add information for hip fracture prediction. Future studies are warranted to determine whether low valine is causally associated with hip fractures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)
- Published
- 2023
- Full Text
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20. Dietary Progesterone Contributes to Intratissue Levels of Progesterone in Male Mice.
- Author
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Colldén H, Hagberg Thulin M, Landin A, Horkeby K, Lagerquist M, Wu J, Nilsson KH, Grahnemo L, Poutanen M, Ryberg H, Vandenput L, and Ohlsson C
- Subjects
- Humans, Cattle, Mice, Male, Animals, Progesterone, Androgen Antagonists, Adrenalectomy, Orchiectomy, Androgens, Prostatic Neoplasms
- Abstract
Progesterone serum levels have been identified as a potential predictor for treatment effect in men with advanced prostate cancer, which is an androgen-driven disease. Although progesterone is the most abundant sex steroid in orchiectomized (ORX) male mice, the origins of progesterone in males are unclear. To determine the origins of progesterone and androgens, we first determined the effect of ORX, adrenalectomy (ADX), or both (ORX + ADX) on progesterone levels in multiple male mouse tissues. As expected, intratissue androgen levels were mainly testicular derived. Interestingly, progesterone levels remained high after ORX and ORX + ADX with the highest levels in white adipose tissue and in the gastrointestinal tract. High progesterone levels were observed in mouse chow and exceptionally high progesterone levels were observed in food items such as dairy, eggs, and beef, all derived from female animals of reproductive age. To determine if orally ingested progesterone contributes to tissue levels of progesterone in males, we treated ORX + ADX and sham mice with isotope-labeled progesterone or vehicle by oral gavage. We observed a significant uptake of labeled progesterone in white adipose tissue and prostate, suggesting that dietary progesterone may contribute to tissue levels of progesterone. In conclusion, although adrenal-derived progesterone contributes to intratissue progesterone levels in males, nonadrenal progesterone sources also contribute. We propose that dietary progesterone is absorbed and contributes to intratissue progesterone levels in male mice. We speculate that food with high progesterone content could be a significant source of progesterone in males, possibly with consequences for men undergoing androgen deprivation therapy for prostate cancer., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)
- Published
- 2023
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21. Identification of three bacterial species associated with increased appendicular lean mass: the HUNT study.
- Author
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Grahnemo L, Nethander M, Coward E, Gabrielsen ME, Sree S, Billod JM, Sjögren K, Engstrand L, Dekkers KF, Fall T, Langhammer A, Hveem K, and Ohlsson C
- Subjects
- Male, Humans, Female, Absorptiometry, Photon, Body Composition, Bone Density, Sarcopenia, Osteoporosis complications
- Abstract
Appendicular lean mass (ALM) associates with mobility and bone mineral density (BMD). While associations between gut microbiota composition and ALM have been reported, previous studies rely on relatively small sample sizes. Here, we determine the associations between prevalent gut microbes and ALM in large discovery and replication cohorts with information on relevant confounders within the population-based Norwegian HUNT cohort (n = 5196, including women and men). We show that the presence of three bacterial species - Coprococcus comes, Dorea longicatena, and Eubacterium ventriosum - are reproducibly associated with higher ALM. When combined into an anabolic species count, participants with all three anabolic species have 0.80 kg higher ALM than those without any. In an exploratory analysis, the anabolic species count is positively associated with femoral neck and total hip BMD. We conclude that the anabolic species count may be used as a marker of ALM and BMD. The therapeutic potential of these anabolic species to prevent sarcopenia and osteoporosis needs to be determined., (© 2023. The Author(s).)
- Published
- 2023
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22. Transplantation of gut microbiota from old mice into young healthy mice reduces lean mass but not bone mass.
- Author
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Lawenius L, Cowardin C, Grahnemo L, Scheffler JM, Horkeby K, Engdahl C, Wu J, Vandenput L, Koskela A, Tuukkanen J, Coward E, Hveem K, Langhammer A, Abrahamsson S, Gordon JI, Sjögren K, and Ohlsson C
- Subjects
- Young Adult, Humans, Mice, Animals, Aged, Infant, Fecal Microbiota Transplantation, Aging, Cecum, Gastrointestinal Microbiome, Microbiota
- Abstract
Aging is associated with low bone and lean mass as well as alterations in the gut microbiota (GM). In this study, we determined whether the reduced bone mass and relative lean mass observed in old mice could be transferred to healthy young mice by GM transplantation (GMT). GM from old (21-month-old) and young adult (5-month-old) donors was used to colonize germ-free (GF) mice in three separate studies involving still growing 5- or 11-week-old recipients and 17-week-old recipients with minimal bone growth. The GM of the recipient mice was similar to that of the donors, demonstrating successful GMT. GM from old mice did not have statistically significant effects on bone mass or bone strength, but significantly reduced the lean mass percentage of still growing recipient mice when compared with recipients of GM from young adult mice. The levels of propionate in the cecum of mice receiving old donor GM were significantly lower than those in mice receiving young adult donor GM. Bacteroides ovatus was enriched in the microbiota of recipient mice harboring GM from young adult donors. The presence of B. ovatus was not only significantly associated with high lean mass percentage in mice, but also with lean mass adjusted for fat mass in the large human HUNT cohort. In conclusion, GM from old mice reduces lean mass percentage but not bone mass in young, healthy, still growing recipient mice. Future studies are warranted to determine whether GM from young mice improves the musculoskeletal phenotype of frail elderly recipient mice.
- Published
- 2023
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23. Assessment of the genetic and clinical determinants of hip fracture risk: Genome-wide association and Mendelian randomization study.
- Author
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Nethander M, Coward E, Reimann E, Grahnemo L, Gabrielsen ME, Wibom C, Mägi R, Funck-Brentano T, Hoff M, Langhammer A, Pettersson-Kymmer U, Hveem K, and Ohlsson C
- Subjects
- Male, Female, Humans, Mendelian Randomization Analysis, Bone Density genetics, Femur Neck, Genome-Wide Association Study, Hip Fractures epidemiology
- Abstract
Hip fracture is the clinically most important fracture, but the genetic architecture of hip fracture is unclear. Here, we perform a large-scale hip fracture genome-wide association study meta-analysis and Mendelian randomization study using five cohorts from European biobanks. The results show that five genetic signals associate with hip fractures. Among these, one signal associates with falls, but not with bone mineral density (BMD), while four signals are in loci known to be involved in bone biology. Mendelian randomization analyses demonstrate a strong causal effect of decreased femoral neck BMD and moderate causal effects of Alzheimer's disease and having ever smoked regularly on risk of hip fractures. The substantial causal effect of decreased femoral neck BMD on hip fractures in both young and old subjects and in both men and women supports the use of change in femoral neck BMD as a surrogate outcome for hip fractures in clinical trials., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2022
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24. Cross-sectional associations between the gut microbe Ruminococcus gnavus and features of the metabolic syndrome.
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Grahnemo L, Nethander M, Coward E, Gabrielsen ME, Sree S, Billod JM, Engstrand L, Abrahamsson S, Langhammer A, Hveem K, and Ohlsson C
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- Clostridiales, Cross-Sectional Studies, Humans, Ruminococcus metabolism, Gastrointestinal Microbiome, Metabolic Syndrome epidemiology
- Abstract
Competing Interests: SS and JMB declare that they are employed at Bio-Me and own Bio-Me stocks. All other authors declare no competing interests. This study was supported by funding from the Swedish Research Council, the Swedish state under the agreement between the Swedish Government and the county councils, the ALF agreement, the Lundberg Foundation, the Torsten Söderberg Foundation, the Novo Nordisk Foundation, and the Knut and Alice Wallenberg Foundation.
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- 2022
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25. A probiotic mix partially protects against castration-induced bone loss in male mice.
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Lawenius L, Colldén H, Horkeby K, Wu J, Grahnemo L, Vandenput L, Ohlsson C, and Sjögren K
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- Animals, Bone Density, Bone and Bones, Female, Femur diagnostic imaging, Humans, Male, Mice, Orchiectomy, Steroids, Bone Diseases, Metabolic etiology, Bone Diseases, Metabolic prevention & control, Probiotics
- Abstract
Studies in postmenopausal women and ovariectomized mice show that the probiotic mix Lacticaseibacillus paracasei DSM13434, Lactiplantibacillus plantarum DSM 15312 and DSM 15313 (L. Mix) can protect from bone loss caused by sex steroid deficiency. Whether probiotic bacteria can protect bone also in sex steroid-deficient males is less studied. We used the orchiectomized mouse as a model for age-dependent bone loss caused by decreasing sex hormone levels in males. We treated 10-week-old male mice with either vehicle (veh) or L. Mix for 6 weeks, starting 2 weeks before orchiectomy (orx) or sham surgery. Importantly, mice treated with L. Mix had a general increase in total body bone mineral density (BMD) and lean mass (P ≤ 0.05) compared with veh-treated mice. Detailed computer tomography analysis of dissected bones showed increased trabecular BMD of the distal metaphyseal region of the femur in L. Mix compared to veh-treated orx mice (+8.0%, P ≤ 0.05). In the vertebra, L. Mix treatment increased trabecular bone volume fraction BV/TV (+11.5%, P ≤ 0.05) compared to veh in orx mice. Also, L. Mix increased the levels of short-chain fatty acids (SCFAs) such as propionate and acetate and important intermediates in SCFA synthesis such as succinate and lactate in the cecal content of male mice. In conclusion, L. Mix treatment resulted in a general increase in BMD in adult male mice and prevented trabecular bone loss in femur and vertebra of orx mice. These bone protective effects of L. Mix were associated with increased levels of SCFAs in the cecal content of male mice.
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- 2022
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26. Acute fat loss does not affect bone mass.
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Lagerquist MK, Gustafsson KL, Henning P, Farman H, Wu J, Sjögren K, Koskela A, Tuukkanen J, Ohlsson C, Wernstedt Asterholm I, and Grahnemo L
- Subjects
- Adipocytes pathology, Animals, Apoptosis, Biomarkers blood, Biomechanical Phenomena, Bone Marrow Cells pathology, Bone Remodeling, Lymphocyte Count, Mice, Transgenic, Organ Size, Spleen pathology, Adiposity, Bone and Bones pathology
- Abstract
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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- 2021
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27. Associations of Trabecular and Cortical Volumetric Bone Mineral Density With Coronary Artery Calcification Score: The Swedish Cardiopulmonary Bioimage Study Pilot Study.
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Funck-Brentano T, Grahnemo L, Hjelmgren O, Brandberg J, Bergström G, and Ohlsson C
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- Coronary Artery Disease diagnostic imaging, Female, Humans, Male, Middle Aged, Osteoporosis diagnostic imaging, Pilot Projects, Sweden epidemiology, Tomography, X-Ray Computed, Vascular Calcification diagnostic imaging, Bone Density, Cancellous Bone diagnostic imaging, Coronary Artery Disease epidemiology, Cortical Bone diagnostic imaging, Femur diagnostic imaging, Osteoporosis epidemiology, Thoracic Vertebrae diagnostic imaging, Vascular Calcification epidemiology
- Published
- 2021
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28. Spleen proteomics data from high fat diet fed mice.
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Svahn SL, Pattanaik B, Grahnemo L, Gutierrez S, Nookaew I, Jansson JO, and Johansson ME
- Abstract
The composition of the diet affects many processes in the body, including body weight and endocrine system. We have previously shown that dietary fat also affects the immune system. Mice fed high fat diet rich in polyunsaturated fatty acids survive S. aureus infection to a much greater extent than mice fed high fat diet rich in saturated fatty acids. Here we present data regarding the dietary effects on protein expression in spleen from mice fed three different diets, I) low fat/chow diet (LFD, n = 4), II) high fat diet rich in saturated fatty acids (HFD-S, n = 4) and III) high fat diet rich in polyunsaturated fatty acids (HFD-P, n = 4). We performed mass spectrophotometry based quantitative proteomics analysis of isolated spleen by implementing the isobaric tags for relative and absolute quantification (iTRAQ) approach. Mass spectrometry data were analyzed using Proteome Discoverer 2.4 software using the search engine mascot against Mus musculus in SwissProt. 924 proteins are identified in all sets ( n = 4) for different dietary effects taken for statistical analysis using Qlucore Omics Explorer software. Only 20 proteins were found to be differentially expressed with a cut-off value of false discovery rate < 0.1 ( q -value) when comparing HFD-S and HFD-P but no differentially expressed proteins were found when LFD was compared with HFD-P or HFD-S. The identified proteins and statistical analysis comparing HFD-S and HFD-P diets are available as a supplementary file S1. We identified a subset of proteins that showed an inverse expression pattern between two high fat diets. These differentially expressed proteins were further classified by gene ontology for their role in biological processes and molecular functions. Mass spectrometry raw data are also available via ProteomeXchange with identifier PXD020365., Competing Interests: The authors declare that they have no known competing for financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article., (© 2020 The Authors.)
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- 2020
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29. Wnt16 Overexpression in Osteoblasts Increases the Subchondral Bone Mass but has no Impact on Osteoarthritis in Young Adult Female Mice.
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Törnqvist AE, Grahnemo L, Nilsson KH, Funck-Brentano T, Ohlsson C, and Movérare-Skrtic S
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- Animals, Cartilage, Articular, Female, Mice, Tibia, Bone Density, Osteoarthritis metabolism, Osteoblasts metabolism, Wnt Proteins metabolism
- Abstract
Epidemiological studies have shown that high bone mineral density (BMD) is associated with an increased risk of osteoarthritis (OA), but the causality of this relationship remains unclear. Both bone mass and OA have been associated with the WNT signaling pathway in genetic studies, there is thus an interest in studying molecular partners of the WNT signaling pathway and OA. Female mice overexpressing WNT16 in osteoblasts (Obl-Wnt16 mice) have an increased bone mass. We aimed to evaluate if the high bone mass in Obl-Wnt16 mice leads to a more severe experimental OA development than in WT control mice. We induced experimental OA in female Obl-Wnt16 and WT control mice by destabilizing the medial meniscus (DMM). The Obl-Wnt16 mice displayed thicker medial and lateral subchondral bone plates as well as increased subchondral trabecular bone volume/tissue volume (BV/TV) but un-altered thickness of articular cartilage compared to WT mice. After DMM surgery, there was no difference in OA severity in the articular cartilage in the knee joint between the Obl-Wnt16 and WT mice. Both the Obl-Wnt16 and WT mice developed osteophytes in the DMM-operated tibia to a similar extent. We conclude that although the Obl-Wnt16 female mice have a high subchondral bone mass due to increased WNT signaling, they do not exhibit a more severe OA phenotype than their WT controls. This demonstrates that high bone mass does not result in an increased risk of OA per se.
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- 2020
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30. Increased bone mass in a mouse model with low fat mass.
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Grahnemo L, Gustafsson KL, Sjögren K, Henning P, Lionikaite V, Koskela A, Tuukkanen J, Ohlsson C, Wernstedt Asterholm I, and Lagerquist MK
- Subjects
- Absorptiometry, Photon, Adipose Tissue metabolism, Animals, Biomarkers blood, Bone and Bones metabolism, Collagen Type I blood, Disease Models, Animal, Inflammation blood, Inflammation diagnostic imaging, Mice, Peptide Fragments blood, Peptides blood, Procollagen blood, Signal Transduction genetics, X-Ray Microtomography, Adipose Tissue diagnostic imaging, Bone Density physiology, Bone and Bones diagnostic imaging, Inflammation metabolism
- Abstract
Mice with impaired acute inflammatory responses within adipose tissue display reduced diet-induced fat mass gain associated with glucose intolerance and systemic inflammation. Therefore, acute adipose tissue inflammation is needed for a healthy expansion of adipose tissue. Because inflammatory disorders are associated with bone loss, we hypothesized that impaired acute adipose tissue inflammation leading to increased systemic inflammation results in a lower bone mass. To test this hypothesis, we used mice overexpressing an adenoviral protein complex, the receptor internalization and degradation (RID) complex that inhibits proinflammatory signaling, under the control of the aP2 promotor (RID tg mice), resulting in suppressed inflammatory signaling in adipocytes. As expected, RID tg mice had lower high-fat diet-induced weight and fat mass gain and higher systemic inflammation than littermate wild-type control mice. Contrary to our hypothesis, RID tg mice had increased bone mass in long bones and vertebrae, affecting trabecular and cortical parameters, as well as improved humeral biomechanical properties. We did not find any differences in bone formation or resorption parameters as determined by histology or enzyme immunoassay. However, bone marrow adiposity, often negatively associated with bone mass, was decreased in male RID tg mice as determined by histological analysis of tibia. In conclusion, mice with reduced fat mass due to impaired adipose tissue inflammation have increased bone mass.
- Published
- 2018
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31. Six Tissue Transcriptomics Reveals Specific Immune Suppression in Spleen by Dietary Polyunsaturated Fatty Acids.
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Svahn SL, Väremo L, Gabrielsson BG, Peris E, Nookaew I, Grahnemo L, Sandberg AS, Wernstedt Asterholm I, Jansson JO, Nielsen J, and Johansson ME
- Subjects
- Adipose Tissue, White drug effects, Adipose Tissue, White metabolism, Animals, Biomarkers metabolism, Blood Glucose metabolism, Energy Metabolism drug effects, Fasting blood, Gene Expression Regulation drug effects, Gene Ontology, Immune System drug effects, Liver drug effects, Liver metabolism, Macrophages drug effects, Macrophages metabolism, Male, Mice, Inbred C57BL, NF-kappa B metabolism, Organ Size drug effects, Phenotype, Principal Component Analysis, Spleen drug effects, Spleen metabolism, Staining and Labeling, Transcriptome genetics, Diet, High-Fat, Fatty Acids, Unsaturated pharmacology, Gene Expression Profiling, Organ Specificity drug effects, Organ Specificity genetics, Spleen immunology
- Abstract
Dietary polyunsaturated fatty acids (PUFA) are suggested to modulate immune function, but the effects of dietary fatty acids composition on gene expression patterns in immune organs have not been fully characterized. In the current study we investigated how dietary fatty acids composition affects the total transcriptome profile, and especially, immune related genes in two immune organs, spleen (SPL) and bone marrow cells (BMC). Four tissues with metabolic function, skeletal muscle (SKM), white adipose tissue (WAT), brown adipose tissue (BAT), and liver (LIV), were investigated as a comparison. Following 8 weeks on low fat diet (LFD), high fat diet (HFD) rich in saturated fatty acids (HFD-S), or HFD rich in PUFA (HFD-P), tissue transcriptomics were analyzed by microarray and metabolic health assessed by fasting blood glucose level, HOMA-IR index, oral glucose tolerance test as well as quantification of crown-like structures in WAT. HFD-P corrected the metabolic phenotype induced by HFD-S. Interestingly, SKM and BMC were relatively inert to the diets, whereas the two adipose tissues (WAT and BAT) were mainly affected by HFD per se (both HFD-S and HFD-P). In particular, WAT gene expression was driven closer to that of the immune organs SPL and BMC by HFDs. The LIV exhibited different responses to both of the HFDs. Surprisingly, the spleen showed a major response to HFD-P (82 genes differed from LFD, mostly immune genes), while it was not affected at all by HFD-S (0 genes differed from LFD). In conclusion, the quantity and composition of dietary fatty acids affected the transcriptome in distinct manners in different organs. Remarkably, dietary PUFA, but not saturated fat, prompted a specific regulation of immune related genes in the spleen, opening the possibility that PUFA can regulate immune function by influencing gene expression in this organ.
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- 2016
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32. Dietary Omega-3 Fatty Acids Increase Survival and Decrease Bacterial Load in Mice Subjected to Staphylococcus aureus-Induced Sepsis.
- Author
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Svahn SL, Ulleryd MA, Grahnemo L, Ståhlman M, Borén J, Nilsson S, Jansson JO, and Johansson ME
- Subjects
- Adipose Tissue, Animals, Cytokines genetics, Cytokines metabolism, Fatty Acids administration & dosage, Fatty Acids pharmacology, Fatty Acids, Omega-3 administration & dosage, Inflammation metabolism, Mice, Random Allocation, Sepsis diet therapy, Staphylococcal Infections microbiology, Bacterial Load drug effects, Fatty Acids, Omega-3 pharmacology, Sepsis microbiology, Staphylococcal Infections diet therapy, Staphylococcus aureus
- Abstract
Sepsis caused by Staphylococcus aureus is increasing in incidence. With the alarming use of antibiotics,S. aureus is prone to become methicillin resistant. Antibiotics are the only widely used pharmacological treatment for sepsis. Interestingly, mice fed high-fat diet (HFD) rich in polyunsaturated fatty acids have better survival of S. aureus-induced sepsis than mice fed HFD rich in saturated fatty acids (HFD-S). To investigate what component of polyunsaturated fatty acids, i.e., omega-3 or omega-6 fatty acids, exerts beneficial effects on the survival of S. aureus-induced sepsis, mice were fed HFD rich in omega-3 or omega-6 fatty acids for 8 weeks prior to inoculation with S. aureus Further, mice fed HFD-S were treated with omega-3 fatty acid metabolites known as resolvins. Mice fed HFD rich in omega-3 fatty acids had increased survival and decreased bacterial loads compared to those for mice fed HFD-S after S. aureus-induced sepsis. Furthermore, the bacterial load was decreased in resolvin-treated mice fed HFD-S after S. aureus-induced sepsis compared with that in mice treated with vehicle. Dietary omega-3 fatty acids increase the survival of S. aureus-induced sepsis by reversing the deleterious effect of HFD-S on mouse survival., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
- Published
- 2016
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33. Regulation of body fat mass by the gut microbiota: Possible mediation by the brain.
- Author
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Schéle E, Grahnemo L, Anesten F, Hallén A, Bäckhed F, and Jansson JO
- Subjects
- Animals, Appetite Regulation, Brain-Derived Neurotrophic Factor physiology, Energy Metabolism, Gastrointestinal Tract metabolism, Gastrointestinal Tract microbiology, Humans, Obesity metabolism, Obesity microbiology, Obesity surgery, Adiposity, Brain physiology, Gastrointestinal Microbiome
- Abstract
New insight suggests gut microbiota as a component in energy balance. However, the underlying mechanisms by which gut microbiota can impact metabolic regulation is unclear. A recent study from our lab shows, for the first time, a link between gut microbiota and energy balance circuitries in the hypothalamus and brainstem. In this article we will review this study further., (Copyright © 2015. Published by Elsevier Inc.)
- Published
- 2016
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34. Suppression of Experimental Arthritis and Associated Bone Loss by a Tissue-Selective Estrogen Complex.
- Author
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Andersson A, Bernardi AI, Nurkkala-Karlsson M, Stubelius A, Grahnemo L, Ohlsson C, Carlsten H, and Islander U
- Subjects
- Animals, Arthritis, Experimental immunology, Arthritis, Rheumatoid immunology, Autoantibodies immunology, Bone Diseases, Metabolic immunology, Cytokines immunology, Female, Femur diagnostic imaging, Femur drug effects, Immunoglobulin G drug effects, Immunoglobulin G immunology, Interleukin-6 immunology, Mice, Ovariectomy, Radiography, Tibia diagnostic imaging, Tibia drug effects, Arthritis, Experimental diagnostic imaging, Arthritis, Rheumatoid diagnostic imaging, Autoantibodies drug effects, Bone Density drug effects, Bone Diseases, Metabolic diagnostic imaging, Cytokines drug effects, Estradiol pharmacology, Estrogens pharmacology, Indoles pharmacology, Selective Estrogen Receptor Modulators pharmacology
- Abstract
In addition to the systemic inflammation present in rheumatoid arthritis (RA), decreased estradiol levels in postmenopausal RA patients further accelerate bone loss in these patients. The tissue-selective estrogen complex (TSEC), an estrogen combined with a selective estrogen receptor modulator, is a new hormone replacement therapy option. The first approved TSEC, containing conjugated estrogens and bazedoxifene (BZA), reduces menopausal symptoms and prevents osteoporosis with an improved safety profile compared with conventional hormone replacement therapy. Previous studies have shown that estrogens strongly inhibit experimental arthritis whereas BZA is mildly suppressive. In this study the antiarthritic potential of combined BZA and estradiol is explored for the first time. Female ovariectomized DBA/1 mice were subjected to collagen-induced arthritis, an experimental postmenopausal RA model, and treated with BZA, 17β-estradiol (E2), combined BZA and E2 (BZA/E2), or vehicle. BZA/E2 suppressed arthritis severity and frequency, synovitis, and joint destruction, equally efficient as E2 alone. Unwanted estrogenic proliferative effects on the endometrium were blocked by the addition of BZA, determined by collecting uterine weights. Bone mineral density was measured by peripheral quantitative computed tomography, and all treatments protected collagen-induced arthritis mice from both trabecular and cortical bone loss. Moreover, BZA/E2, but not E2 alone, inhibited preosteoclast formation and reduced serum anticollagen type II antibodies. In conclusion, a TSEC, herein combined BZA/E2, suppresses experimental arthritis and prevents associated bone loss as efficiently as E2 alone but with minimal uterine effects, highlighting the need for clinical trials that evaluate the addition of a TSEC to conventional postmenopausal RA treatment.
- Published
- 2016
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35. Enzalutamide Reduces the Bone Mass in the Axial But Not the Appendicular Skeleton in Male Mice.
- Author
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Wu J, Movérare-Skrtic S, Börjesson AE, Lagerquist MK, Sjögren K, Windahl SH, Koskela A, Grahnemo L, Islander U, Wilhelmson AS, Tivesten Å, Tuukkanen J, and Ohlsson C
- Subjects
- Absorptiometry, Photon, Animals, Benzamides, Femur diagnostic imaging, Lumbar Vertebrae diagnostic imaging, Male, Mice, Nitriles, Orchiectomy, Organ Size drug effects, Phenylthiohydantoin pharmacology, Spine diagnostic imaging, Spine drug effects, Tibia diagnostic imaging, X-Ray Microtomography, Androgen Receptor Antagonists pharmacology, Antineoplastic Agents, Hormonal pharmacology, Bone Density drug effects, Bone Remodeling drug effects, Femur drug effects, Lumbar Vertebrae drug effects, Phenylthiohydantoin analogs & derivatives, Tibia drug effects
- Abstract
Testosterone is a crucial regulator of the skeleton, but the role of the androgen receptor (AR) for the maintenance of the adult male skeleton is unclear. In the present study, the role of the AR for bone metabolism and skeletal growth after sexual maturation was evaluated by means of the drug enzalutamide, which is a new AR antagonist used in the treatment of prostate cancer patients. Nine-week-old male mice were treated with 10, 30, or 100 mg/kg·d of enzalutamide for 21 days or were surgically castrated and were compared with vehicle-treated gonadal intact mice. Although orchidectomy reduced the cortical bone thickness and trabecular bone volume fraction in the appendicular skeleton, these parameters were unaffected by enzalutamide. In contrast, both enzalutamide and orchidectomy reduced the bone mass in the axial skeleton as demonstrated by a reduced lumbar spine areal bone mineral density (P < .001) and trabecular bone volume fraction in L5 vertebrae (P < .001) compared with vehicle-treated gonadal intact mice. A compression test of the L5 vertebrae revealed that the mechanical strength in the axial skeleton was significantly reduced by enzalutamide (maximal load at failure -15.3% ± 3.5%; P < .01). The effects of enzalutamide in the axial skeleton were associated with a high bone turnover. In conclusion, enzalutamide reduces the bone mass in the axial but not the appendicular skeleton in male mice after sexual maturation. We propose that the effect of testosterone on the axial skeleton in male mice is mainly mediated via the AR.
- Published
- 2016
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36. IL-17-producing γδT cells are regulated by estrogen during development of experimental arthritis.
- Author
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Andersson A, Grahnemo L, Engdahl C, Stubelius A, Lagerquist MK, Carlsten H, and Islander U
- Subjects
- Animals, Arthritis, Experimental metabolism, Cell Movement drug effects, Cell Movement immunology, Enzyme-Linked Immunospot Assay, Estrogens pharmacology, Female, Interleukin-17 metabolism, Joints drug effects, Joints immunology, Lymph Nodes drug effects, Lymph Nodes immunology, Lymphocyte Count, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Knockout, Receptors, Antigen, T-Cell, gamma-delta immunology, Receptors, Antigen, T-Cell, gamma-delta metabolism, Receptors, CCR6 immunology, Receptors, CCR6 metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Th17 Cells drug effects, Th17 Cells immunology, Th17 Cells metabolism, Arthritis, Experimental immunology, Estradiol pharmacology, Interleukin-17 immunology, T-Lymphocytes drug effects
- Abstract
Interleukin-17 (IL-17) drives inflammation and destruction of joints in rheumatoid arthritis (RA). The female sex hormone 17β-estradiol (E2) inhibits experimental arthritis. γδT cells are significant producers of IL-17, thus the aim of this study was to investigate if E2 influenced IL-17(+) γδT cells during arthritis development using a variety of experimental RA models: collagen-induced arthritis (CIA); antigen-induced arthritis (AIA); and collagen antibody-induced arthritis (CAIA). We demonstrate that E2 treatment decreases IL-17(+) γδT cell number in joints, but increases IL-17(+) γδT cells in draining lymph nodes, suggesting an E2-mediated prevention of IL-17(+) γδT cell migration from lymph nodes to joints, in concert with our recently reported effects of E2 on Th17 cells (Andersson et al., 2015). E2 did neither influence the general γδT cell population nor IFNγ(+) γδT cells, implying a selective regulation of IL-17-producing cells. In conclusion, this study contributes to the understanding of estrogen's role in autoimmune disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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37. Selective estrogen receptor modulators in T cell development and T cell dependent inflammation.
- Author
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Bernardi AI, Andersson A, Stubelius A, Grahnemo L, Carlsten H, and Islander U
- Subjects
- Animals, Disease Models, Animal, Female, Humans, Hypersensitivity, Delayed immunology, Hypersensitivity, Delayed pathology, Lymphopoiesis immunology, Mice, Osteoporosis, Postmenopausal drug therapy, Osteoporosis, Postmenopausal pathology, T-Lymphocytes pathology, Estrogen Antagonists pharmacology, Estrogens pharmacology, Lymphopoiesis drug effects, Osteoporosis, Postmenopausal immunology, Receptors, Estrogen immunology, T-Lymphocytes immunology
- Abstract
Lasofoxifene (las) and bazedoxifene (bza) are third generation selective estrogen receptor modulators (SERMs) with minimal estrogenic side effects, approved for treatment of postmenopausal osteoporosis. T cells are involved in the pathology of postmenopausal osteoporosis and previous studies have established an important role for 17β-estradiol (E2) in T cell development and function. E2 causes a drastic thymic atrophy, alters the composition of thymic T cell populations, and inhibits T cell dependent inflammation. In contrast, the second generation SERM raloxifene (ral) lacks these properties. Although las and bza are drugs approved for treatment of postmenopausal bone loss, it is of importance to study their effects on other biological aspects in order to extend the potential use of these compounds. Therefore, the aim of this study was to investigate if treatment with las and bza affects T lymphopoiesis and T cell dependent inflammation. C57Bl6 mice were ovariectomized (ovx) and treated with vehicle, E2, ral, las or bza. As expected, E2 reduced both thymus weight and decreased the proportion of early T cell progenitors while increasing more mature T cell populations in the thymus. E2 also suppressed the T cell dependent delayed-type hypersensitivity (DTH) reaction to oxazolone (OXA). Ral and las, but not bza, decreased thymus weight, while none of the SERMs had any effects on T cell populations in the thymus or on inflammation in DTH. In conclusion, this study shows that treatment with las or bza does not affect T lymphopoiesis or T cell dependent inflammation., (Copyright © 2015 The Authors. Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2015
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38. Trabecular bone loss in collagen antibody-induced arthritis.
- Author
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Grahnemo L, Andersson A, Nurkkala-Karlsson M, Stubelius A, Lagerquist MK, Svensson MN, Ohlsson C, Carlsten H, and Islander U
- Subjects
- Animals, Antibodies immunology, Antibodies toxicity, Arthritis, Experimental chemically induced, Arthritis, Experimental immunology, Female, Humans, Mice, Mice, Inbred C57BL, Osteoporosis, Postmenopausal chemically induced, Osteoporosis, Postmenopausal immunology, Arthritis, Experimental pathology, Disease Models, Animal, Osteoporosis, Postmenopausal pathology
- Abstract
Introduction: Postmenopausal women with rheumatoid arthritis (RA) have increased risk of developing osteoporosis due to chronic inflammation and estrogen deprivation. Collagen antibody-induced arthritis (CAIA), an experimental polyarthritis model representing the effector phase of arthritis, is mainly mediated by the innate immune system. Compared to the widely used collagen-induced arthritis model, CAIA is conveniently short and can be used in C57BL/6 mice, enabling studies with knock-out mice. However, the impact on bone of the CAIA model in C57BL/6 mice has not previously been studied. Therefore, the aim of this study was to determine if CAIA can be used to study postmenopausal arthritis-induced osteoporosis., Methods: CAIA was induced by administration of collagen-type II antibodies and lipopolysaccharide to ovariectomized female C57BL/6J mice. Control mice received lipopolysaccharide, but no antibodies. Nine days later, femurs were collected for high-resolution micro-CT and histomorphometry. Serum was used to assess cartilage breakdown and levels of complement. Frequencies of immune cell subsets from bone marrow and lymph nodes were analyzed by flow cytometery., Results: Trabecular bone mass was decreased and associated with increased number of osteoclasts per bone surface in the CAIA model. Also, the frequency of interleukin-17(+) cells in lymph nodes was increased in CAIA., Conclusion: The present study show that CAIA, a short reproducible arthritis model that is compatible with C57BL/6 mice, is associated with increased number of osteoclasts and trabecular bone loss.
- Published
- 2015
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39. Estrogen regulates T helper 17 phenotype and localization in experimental autoimmune arthritis.
- Author
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Andersson A, Stubelius A, Karlsson MN, Engdahl C, Erlandsson M, Grahnemo L, Lagerquist MK, and Islander U
- Subjects
- Animals, Arthritis, Experimental immunology, Chemokine CCL20 metabolism, Estrogen Receptor alpha genetics, Female, Flow Cytometry, Immunophenotyping, Lymph Nodes cytology, Mice, Mice, Inbred DBA, Mice, Knockout, Ovariectomy, Receptors, CCR6 metabolism, Sex Factors, Th17 Cells metabolism, Arthritis, Experimental drug therapy, Estradiol pharmacology, Estrogens pharmacology, Th17 Cells immunology
- Abstract
Introduction: The incidence and progression of many autoimmune diseases are sex-biased, which might be explained by the immunomodulating properties of endocrine hormones. Treatment with estradiol potently inhibits experimental autoimmune arthritis. Interleukin-17-producing T helper cells (Th17) are key players in several autoimmune diseases, particularly in rheumatoid arthritis. The aim of this study was to investigate the effects of estrogen on Th17 cells in experimental arthritis., Methods: Ovariectomized DBA/1 mice treated with 17β-estradiol (E2) or placebo were subjected to collagen-induced arthritis (CIA), and arthritis development was assessed. Th17 cells in joints and lymph nodes were studied by flow cytometry. Lymph node Th17 cells were also examined in ovariectomized estrogen receptor α-knockout mice (ERα-/-) and wild-type littermates, treated with E2 or placebo and subjected to antigen-induced arthritis., Results: E2-treated mice with established CIA showed reduced severity of arthritis and fewer Th17 cells in joints compared with controls. Interestingly, E2-treated mice displayed increased Th17 cells in lymph nodes during the early phase of the disease, dependent on ERα. E2 increased the expression of C-C chemokine receptor 6 (CCR6) on lymph node Th17 cells as well as the expression of the corresponding C-C chemokine ligand 20 (CCL20) within lymph nodes., Conclusions: This is the first study in which the effects of E2 on Th17 cells have been characterized in experimental autoimmune arthritis. We report that E2 treatment results in an increase of Th17 cells in lymph nodes during the early phase of arthritis development, but leads to a decrease of Th17 in joints during established arthritis. Our data suggest that this may be caused by interference with the CCR6-CCL20 pathway, which is important for Th17 cell migration. This study contributes to the understanding of the role of estrogen in the development of autoimmune arthritis and opens up new fields for research concerning the sex bias in autoimmune disease.
- Published
- 2015
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40. Dietary polyunsaturated fatty acids increase survival and decrease bacterial load during septic Staphylococcus aureus infection and improve neutrophil function in mice.
- Author
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Svahn SL, Grahnemo L, Pálsdóttir V, Nookaew I, Wendt K, Gabrielsson B, Schéle E, Benrick A, Andersson N, Nilsson S, Johansson ME, and Jansson JO
- Subjects
- Animals, Bone Marrow Cells immunology, Cathepsin D biosynthesis, Chemotaxis immunology, Diet, Diet, High-Fat adverse effects, Inflammation chemically induced, Inflammation immunology, Male, Mice, Mice, Inbred C57BL, Sepsis immunology, Sepsis microbiology, Staphylococcus aureus immunology, Thioglycolates, Bacterial Load drug effects, Dietary Fats, Unsaturated immunology, Fatty Acids, Unsaturated administration & dosage, Neutrophils immunology, Staphylococcal Infections immunology
- Abstract
Severe infection, including sepsis, is an increasing clinical problem that causes prolonged morbidity and substantial mortality. At present, antibiotics are essentially the only pharmacological treatment for sepsis. The incidence of resistance to antibiotics is increasing; therefore, it is critical to find new therapies for sepsis. Staphylococcus aureus is a major cause of septic mortality. Neutrophils play an important role in the defense against bacterial infections. We have shown that a diet with high levels of dietary saturated fatty acids decreases survival in septic mice, but the mechanisms behind this remain elusive. The aim of the present study was to investigate how the differences in dietary fat composition affect survival and bacterial load after experimental septic infection and neutrophil function in uninfected mice. We found that, after S. aureus infection, mice fed a polyunsaturated high-fat diet (HFD-P) for 8 weeks had increased survival and decreased bacterial load during sepsis compared with mice fed a saturated high-fat diet (HFD-S), similar to mice fed a low-fat diet (LFD). Uninfected mice fed HFD-P had a higher frequency of neutrophils in bone marrow than mice fed HFD-S. In addition, mice fed HFD-P had a higher frequency of neutrophils recruited to the site of inflammation in response to peritoneal injection of thioglycolate than mice fed HFD-S. Differences between the proportion of dietary protein and carbohydrate did not affect septic survival at all. In conclusion, polyunsaturated dietary fat increased both survival and efficiency of bacterial clearance during septic S. aureus infection. Moreover, this diet increased the frequency and chemotaxis of neutrophils, key components of the immune response to S. aureus infections., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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41. Possible role of lymphocytes in glucocorticoid-induced increase in trabecular bone mineral density.
- Author
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Grahnemo L, Jochems C, Andersson A, Engdahl C, Ohlsson C, Islander U, and Carlsten H
- Subjects
- Animals, Bone and Bones drug effects, Dexamethasone pharmacology, Female, Femur drug effects, Lymphocytes drug effects, Mice, Mice, Inbred C57BL, Mice, SCID, Osteogenesis drug effects, Up-Regulation drug effects, X-Ray Microtomography, Bone Density drug effects, Glucocorticoids pharmacology, Lymphocytes physiology
- Abstract
Treatment with anti-inflammatory glucocorticoids is associated with osteoporosis. Many of the treated patients are postmenopausal women, who even without treatment have an increased risk of osteoporosis. Lymphocytes have been shown to play a role in postmenopausal and arthritis-induced osteoporosis, and they are targeted by glucocorticoids. The aim of this study was to investigate the mechanisms behind effects of glucocorticoids on bone during health and menopause, focusing on lymphocytes. Female C57BL/6 or SCID mice were therefore sham-operated or ovariectomized and 2 weeks later treatment with dexamethasone (dex), the nonsteroidal anti-inflammatory drug carprofen, or vehicle was started and continued for 2.5 weeks. At the termination of experiments, femurs were phenotyped using peripheral quantitative computed tomography and high-resolution micro-computed tomography, and markers of bone turnover were analyzed in serum. T and B lymphocyte populations in bone marrow and spleen were analyzed by flow cytometry. Dex-treated C57BL/6 mice had increased trabecular bone mineral density, but lower cortical content and thickness compared with vehicle-treated mice. The dex-treated mice also had lower levels of bone turnover markers and markedly decreased numbers of spleen T and B lymphocytes. In contrast, these effects could not be repeated when mice were treated with the nonsteroidal anti-inflammatory drug carprofen. In addition, dex did not increase trabecular bone in ovariectomized SCID mice lacking functional T and B lymphocytes. In contrast to most literature, the results from this study indicate that treatment with dex increased trabecular bone density, which may indicate that this effect is associated with corticosteroid-induced alterations of the lymphocyte populations., (© 2015 The authors.)
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- 2015
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42. Effects of lasofoxifene and bazedoxifene on B cell development and function.
- Author
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Bernardi AI, Andersson A, Grahnemo L, Nurkkala-Karlsson M, Ohlsson C, Carlsten H, and Islander U
- Abstract
The third generation selective estrogen receptor modulators lasofoxifene (las) and bazedoxifene (bza) are indicated for treatment of postmenopausal osteoporosis. 17β-Estradiol (E2) and the second generation SERM raloxifene (ral) have major effects on the immune system, particularly on B cells. Treatment with E2 or ral inhibits B lymphopoiesis and treatment with E2, but not ral, stimulates antibody production. The effects of las and bza on the immune system have not been studied. Therefore, the aim of this study was to investigate their role in B cell development, maturation, and function. C57BL/6 mice were sham-operated or ovariectomized (ovx) and treated with vehicle, E2, ral, las, or bza. All substances increased total bone mineral density in ovx mice, as measured by peripheral quantitative computed tomography. In uterus, bza alone lacked agonistic effect in ovx mice and even acted as an antagonist in sham mice. As expected, E2 decreased B cell numbers at all developmental stages from pre-BI cells (in bone marrow) to transitional 1 (T1) B cells (in spleen) and increased marginal zone (MZ) B cells as determined by flow cytometry. However, treatment with las or bza only decreased the last stages of bone marrow B cell development and splenic T1 B cells, but had no effect MZ B cells. E2 increased antibody-producing cells quantified by ELISPOT, but las or bza did not. In conclusion, las and bza differ from E2 by retaining normal number of cells at most B cell stages during B lymphopoiesis and maturation and by not increasing antibody-producing cells.
- Published
- 2014
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43. The gut microbiota reduces leptin sensitivity and the expression of the obesity-suppressing neuropeptides proglucagon (Gcg) and brain-derived neurotrophic factor (Bdnf) in the central nervous system.
- Author
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Schéle E, Grahnemo L, Anesten F, Hallén A, Bäckhed F, and Jansson JO
- Subjects
- Adiposity, Agouti-Related Protein genetics, Agouti-Related Protein metabolism, Animals, Brain Stem metabolism, Brain-Derived Neurotrophic Factor genetics, Germ-Free Life, Hypothalamus metabolism, Injections, Intraperitoneal, Leptin administration & dosage, Leptin blood, Leptin genetics, Male, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Neuropeptide Y genetics, Neuropeptide Y metabolism, Pro-Opiomelanocortin genetics, Pro-Opiomelanocortin metabolism, Proglucagon genetics, Recombinant Proteins administration & dosage, Recombinant Proteins metabolism, Suppressor of Cytokine Signaling 3 Protein, Suppressor of Cytokine Signaling Proteins genetics, Suppressor of Cytokine Signaling Proteins metabolism, Brain-Derived Neurotrophic Factor metabolism, Central Nervous System metabolism, Down-Regulation, Intestines microbiology, Leptin metabolism, Neurons metabolism, Proglucagon metabolism
- Abstract
The gut microbiota contributes to fat mass and the susceptibility to obesity. However, the underlying mechanisms are not completely understood. To investigate whether the gut microbiota affects hypothalamic and brainstem body fat-regulating circuits, we compared gene expression of food intake-regulating neuropeptides between germ-free and conventionally raised (CONV-R) mice. We found that CONV-R mice had decreased expression of the antiobesity neuropeptide glucagon-like peptide-1 (GLP-1) precursor proglucagon (Gcg) in the brainstem. Moreover, in both the hypothalamus and the brainstem, CONV-R mice had decreased expression of the antiobesity neuropeptide brain-derived neurotrophic factor (Bdnf). CONV-R mice had reduced expression of the pro-obesity peptides neuropeptide-Y (Npy) and agouti-related protein (Agrp), and increased expression of the antiobesity peptides proopiomelanocortin (Pomc) and cocaine- and amphetamine-regulated transcript (Cart) in the hypothalamus. The latter changes in neuropeptide expression could be secondary to elevated fat mass in CONV-R mice. Leptin treatment caused less weight reduction and less suppression of orexigenic Npy and Agrp expression in CONV-R mice compared with germ-free mice. The hypothalamic expression of leptin resistance-associated suppressor of cytokine signaling 3 (Socs-3) was increased in CONV-R mice. In conclusion, the gut microbiota reduces the expression of 2 genes coding for body fat-suppressing neuropeptides, Gcg and Bdnf, an alteration that may contribute to fat mass induction by the gut microbiota. Moreover, the presence of body fat-inducing gut microbiota is associated with hypothalamic signs of Socs-3-mediated leptin resistance, which may be linked to failed compensatory body fat reduction.
- Published
- 2013
- Full Text
- View/download PDF
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