| 1. |
- Brommage, Robert, et al.
(författare)
-
High Fidelity of Mouse Models Mimicking Human Genetic Skeletal Disorders
- 2020
-
Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- The 2019 International Skeletal Dysplasia Society nosology update lists 441 genes for which mutations result in rare human skeletal disorders. These genes code for enzymes (33%), scaffolding proteins (18%), signal transduction proteins (16%), transcription factors (14%), cilia proteins (8%), extracellular matrix proteins (5%), and membrane transporters (4%). Skeletal disorders include aggrecanopathies, channelopathies, ciliopathies, cohesinopathies, laminopathies, linkeropathies, lysosomal storage diseases, protein-folding and RNA splicing defects, and ribosomopathies. With the goal of evaluating the ability of mouse models to mimic these human genetic skeletal disorders, a PubMed literature search identified 260 genes for which mutant mice were examined for skeletal phenotypes. These mouse models included spontaneous and ENU-induced mutants, global and conditional gene knockouts, and transgenic mice with gene over-expression or specific base-pair substitutions. The human X-linked gene ARSE and small nuclear RNA U4ATAC, a component of the minor spliceosome, do not have mouse homologs. Mouse skeletal phenotypes mimicking human skeletal disorders were observed in 249 of the 260 genes (96%) for which comparisons are possible. A supplemental table in spreadsheet format provides PubMed weblinks to representative publications of mutant mouse skeletal phenotypes. Mutations in 11 mouse genes (Ccn6, Cyp2r1, Flna, Galns, Gna13, Lemd3, Manba, Mnx1, Nsd1, Plod1, Smarcal1) do not result in similar skeletal phenotypes observed with mutations of the homologous human genes. These discrepancies can result from failure of mouse models to mimic the exact human gene mutations. There are no obvious commonalities among these 11 genes. Body BMD and/or radiologic dysmorphology phenotypes were successfully identified for 28 genes by the International Mouse Phenotyping Consortium (IMPC). Forward genetics using ENU mouse mutagenesis successfully identified 37 nosology gene phenotypes. Since many human genetic disorders involve hypomorphic, gain-of-function, dominant-negative and intronic mutations, future studies will undoubtedly utilize CRISPR/Cas9 technology to examine transgenic mice having genes modified to exactly mimic variant human sequences. Mutant mice will increasingly be employed for drug development studies designed to treat human genetic skeletal disorders.
|
|
| 2. |
- Brommage, Robert, et al.
(författare)
-
NOTUM inhibition increases endocortical bone formation and bone strength
- 2019
-
Ingår i: Bone Research. - : Springer Science and Business Media LLC. - 2095-4700 .- 2095-6231. ; 7:2
-
Tidskriftsartikel (refereegranskat)abstract
- The disability, mortality and costs caused by non-vertebral osteoporotic fractures are enormous. Existing osteoporosis therapies are highly effective at reducing vertebral but not non-vertebral fractures. Cortical bone is a major determinant of non-vertebral bone strength. To identify novel osteoporosis drug targets, we phenotyped cortical bone of 3 366 viable mouse strains with global knockouts of druggable genes. Cortical bone thickness was substantially elevated in Notum(-/-) mice. NOTUM is a secreted WNT lipase and we observed high NOTUM expression in cortical bone and osteoblasts but not osteoclasts. Three orally active small molecules and a neutralizing antibody inhibiting NOTUM lipase activity were developed. They increased cortical bone thickness and strength at multiple skeletal sites in both gonadal intact and ovariectomized rodents by stimulating endocortical bone formation. Thus, inhibition of NOTUM activity is a potential novel anabolic therapy for strengthening cortical bone and preventing non-vertebral fractures.
|
|
| 3. |
- Brommage, Robert, et al.
(författare)
-
Translational studies provide insights for the etiology and treatment of cortical bone osteoporosis
- 2018
-
Ingår i: Best Practice & Research Clinical Endocrinology & Metabolism. - : Elsevier BV. - 1521-690X. ; 32:3, s. 329-340
-
Tidskriftsartikel (refereegranskat)abstract
- Increasing attention is being focused on the important contributions of cortical bone to bone strength, fractures and osteoporosis therapies. Recent progress in human genome wide association studies in combination with high-throughput mouse gene knockout phenotyping efforts of multiple genes and advanced conditional gene inactivation in mouse models have successfully identified genes with crucial roles in cortical bone homeostasis. Particular attention in this review is given to genes, such as WNT16, POSTN and SFRP4, that differentially affect cortical and trabecular bone architecture. We propose that animal models of cortical bone metabolism will substantially contribute to developing anabolic osteoporosis therapies that improve cortical bone mass and reduce non-vertebral fracture risk. 0 (C) 2018 Elsevier Ltd. All rights reserved.
|
|
| 4. |
- Funck-Brentano, Thomas, et al.
(författare)
-
Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice
- 2018
-
Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 238:1, s. 13-23
-
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.
|
|
| 5. |
- Medina-Gomez, Carolina, et al.
(författare)
-
Meta-Analysis of Genome-Wide Scans for Total Body BMD in Children and Adults Reveals Allelic Heterogeneity and Age-Specific Effects at the WNT16 Locus.
- 2012
-
Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:7
-
Tidskriftsartikel (refereegranskat)abstract
- To identify genetic loci influencing bone accrual, we performed a genome-wide association scan for total-body bone mineral density (TB-BMD) variation in 2,660 children of different ethnicities. We discovered variants in 7q31.31 associated with BMD measurements, with the lowest P = 4.1×10(-11) observed for rs917727 with minor allele frequency of 0.37. We sought replication for all SNPs located ±500 kb from rs917727 in 11,052 additional individuals from five independent studies including children and adults, together with de novo genotyping of rs3801387 (in perfect linkage disequilibrium (LD) with rs917727) in 1,014 mothers of children from the discovery cohort. The top signal mapping in the surroundings of WNT16 was replicated across studies with a meta-analysis P = 2.6×10(-31) and an effect size explaining between 0.6%-1.8% of TB-BMD variance. Conditional analyses on this signal revealed a secondary signal for total body BMD (P = 1.42×10(-10)) for rs4609139 and mapping to C7orf58. We also examined the genomic region for association with skull BMD to test if the associations were independent of skeletal loading. We identified two signals influencing skull BMD variation, including rs917727 (P = 1.9×10(-16)) and rs7801723 (P = 8.9×10(-28)), also mapping to C7orf58 (r(2) = 0.50 with rs4609139). Wnt16 knockout (KO) mice with reduced total body BMD and gene expression profiles in human bone biopsies support a role of C7orf58 and WNT16 on the BMD phenotypes observed at the human population level. In summary, we detected two independent signals influencing total body and skull BMD variation in children and adults, thus demonstrating the presence of allelic heterogeneity at the WNT16 locus. One of the skull BMD signals mapping to C7orf58 is mostly driven by children, suggesting temporal determination on peak bone mass acquisition. Our life-course approach postulates that these genetic effects influencing peak bone mass accrual may impact the risk of osteoporosis later in life.
|
|
| 6. |
- Zheng, Hou-Feng, et al.
(författare)
-
WNT16 influences bone mineral density, Cortical bone thickness, bone strength, and Osteoporotic fracture risk
- 2012
-
Ingår i: PLoS genetics. - SAN FRANCISCO, USA : PUBLIC LIBRARY SCIENCE. - 1553-7404. ; 8:7, s. e1002745-
-
Tidskriftsartikel (refereegranskat)abstract
- We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2×10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3×10(-12), and -0.16 SD per G allele, P = 1.2×10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10(-6) and rs2707466: OR = 1.22, P = 7.2×10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5×10(-13)
|
|
| 7. |
|
|
