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| 2. |
- Funck-Brentano, Thomas, et al.
(författare)
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Causal Factors for Knee, Hip, and Hand Osteoarthritis: A Mendelian Randomization Study in the UK Biobank
- 2019
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 71:10, s. 1634-1641
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Tidskriftsartikel (refereegranskat)abstract
- Objective There is no curative treatment for osteoarthritis (OA), which is the most common form of arthritis. This study was undertaken to identify causal risk factors of knee, hip, and hand OA. Methods Individual-level data from 384,838 unrelated participants in the UK Biobank study were analyzed. Mendelian randomization (MR) analyses were performed to test for causality for body mass index (BMI), bone mineral density (BMD), serum high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride levels, type 2 diabetes, systolic blood pressure (BP), and C-reactive protein (CRP) levels. The primary outcome measure was OA determined using hospital diagnoses (all sites, n = 48,431; knee, n = 19,727; hip, n = 11,875; hand, n = 2,330). Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Results MR analyses demonstrated a robust causal association of genetically determined BMI with all OA (OR per SD increase 1.57 [95% CI 1.44-1.71]), and with knee OA and hip OA, but not with hand OA. Increased genetically determined femoral neck BMD was causally associated with all OA (OR per SD increase 1.14 [95% CI 1.06-1.22]), knee OA, and hip OA. Low systolic BP was causally associated with all OA (OR per SD decrease 1.55 [95% CI 1.29-1.87]), knee OA, and hip OA. There was no evidence of causality for the other tested metabolic factors or CRP level. Conclusion Our findings indicate that BMI exerts a major causal effect on the risk of OA at weight-bearing joints, but not at the hand. Evidence of causality of all OA, knee OA, and hip OA was also observed for high femoral neck BMD and low systolic BP. However, we found no evidence of causality for other metabolic factors or CRP level.
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| 3. |
- Funck-Brentano, Thomas, et al.
(författare)
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Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice
- 2018
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Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 238:1, s. 13-23
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Tidskriftsartikel (refereegranskat)abstract
- WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, mu CT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.
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| 4. |
- Funck-Brentano, Thomas, et al.
(författare)
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Reply.
- 2019
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Ingår i: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 71:12
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Tidskriftsartikel (refereegranskat)
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| 5. |
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| 6. |
- Moverare-Skrtic, Sofia, et al.
(författare)
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Osteoblast-derived NOTUM reduces cortical bone mass in mice and the NOTUM locus is associated with bone mineral density in humans
- 2019
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Ingår i: Faseb Journal. - 0892-6638. ; 33:10, s. 11163-11179
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis is a common skeletal disease, affecting millions of individuals worldwide. Currently used osteoporosis treatments substantially reduce vertebral fracture risk, whereas nonvertebral fracture risk, mainly caused by reduced cortical bone mass, has only moderately been improved by the osteoporosis drugs used, defining an unmet medical need. Because several wingless-type MMTV integration site family members (WNTs) and modulators of WNT activity are major regulators of bone mass, we hypothesized that NOTUM, a secreted WNT lipase, might modulate bone mass via an inhibition of WNT activity. To characterize the possible role of endogenous NOTUM as a physiologic modulator of bone mass, we developed global, cell-specific, and inducible Notum-inactivated mouse models. Notum expression was high in the cortical bone in mice, and conditional Notum inactivation revealed that osteoblast lineage cells are the principal source of NOTUM in the cortical bone. Osteoblast lineage-specific Notum inactivation increased cortical bone thickness via an increased periosteal circumference. Inducible Notum inactivation in adult mice increased cortical bone thickness as a result of increased periosteal bone formation, and silencing of Notum expression in cultured osteoblasts enhanced osteoblast differentiation. Large-scale human genetic analyses identified genetic variants mapping to the NOTUM locus that are strongly associated with bone mineral density (BMD) as estimated with quantitative ultrasound in the heel. Thus, osteoblast-derived NOTUM is an essential local physiologic regulator of cortical bone mass via effects on periosteal bone formation in adult mice, and genetic variants in the NOTUM locus are associated with BMD variation in adult humans. Therapies targeting osteoblast-derived NOTUM may prevent nonvertebral fractures.-Moverare-Skrtic, S., Nilsson, K. H., Henning, P., Funck-Brentano, T., Nethander, M., Rivadeneira, F., Coletto Nunes, G., Koskela, A., Tuukkanen, J., Tuckermann, J., Perret, C., Souza, P. P. C., Lerner, U. H., Ohlsson, C. Osteoblast-derived NOTUM reduces cortical bone mass in mice and the NOTUM locus is associated with bone mineral density in humans.
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| 7. |
- Nethander, Maria, 1980, et al.
(författare)
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An atlas of genetic determinants of forearm fracture.
- 2023
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Ingår i: Nature genetics. - : Springer Nature. - 1546-1718 .- 1061-4036. ; 55:11, s. 1820-1830
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Tidskriftsartikel (refereegranskat)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.
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| 8. |
- Nethander, Maria, 1980, et al.
(författare)
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Assessment of the genetic and clinical determinants of hip fracture risk: Genome-wide association and Mendelian randomization study.
- 2022
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Ingår i: Cell reports. Medicine. - : Elsevier BV. - 2666-3791. ; 3:10
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Tidskriftsartikel (refereegranskat)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.
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| 9. |
- Nethander, Maria, 1980, et al.
(författare)
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Evidence of a Causal Effect of Estradiol on Fracture Risk in Men.
- 2019
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 104:2, s. 433-442
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Tidskriftsartikel (refereegranskat)abstract
- Observational studies indicate that serum estradiol (E2) is more strongly associated with bone mineral density (BMD) than serum testosterone (T) while both E2 and T associate with fracture risk in men.To evaluate the possible causal effect of serum E2 and T on fracture risk in men.A Mendelian Randomization (MR) approach was undertaken using individual-level data of genotypes, BMD as estimated by quantitative ultrasound of the heel (eBMD), fractures (n=17,650), and relevant covariates of 175,583 unrelated men of European origin from the UK Biobank. The genetic instruments for serum E2 and T were taken from the most recent large scale GWAS meta-analyses on these hormones in men.MR analyses demonstrated a causal effect of serum E2 on eBMD and fracture risk. A 1 SD (or 9.6 pg/ml) genetically instrumented decrease in serum E2 was associated with a 0.38 SD decrease in eBMD (p-value 9.7 x 10-74) and an increased risk of any fracture (OR 1.35, 95% CI, 1.18-1.55), non-vertebral major osteoporotic fractures (OR 1.75, 95% CI, 1.35-2.27) and wrist fractures (OR 2.27, 95% CI, 1.62-3.16). These causal effects of serum E2 on fracture risk were robust in sensitivity analyses and remained unchanged in stratified analyses for age, BMI, eBMD, smoking status, and physical activity. MR analyses revealed no evidence of a causal effect of T levels on fracture risk.Our findings provide the first evidence of a robust causal effect of serum E2, but not T, on fracture risk in men.
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| 10. |
- Törnqvist, Anna E, et al.
(författare)
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Wnt16 Overexpression in Osteoblasts Increases the Subchondral Bone Mass but has no Impact on Osteoarthritis in Young Adult Female Mice
- 2020
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 107:1, s. 31-40
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Tidskriftsartikel (refereegranskat)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. © 2020, The Author(s).
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