المؤلفون: Kuhns, Benjamin D, Reuter, John M, Hansen, Victoria L, Soles, Gillian L, Jonason, Jennifer H, Ackert‐Bicknell, Cheryl L, Wu, Chia‐Lung, Giordano, Brian D

المصدر: Journal of Orthopaedic Research®. 41(7)

مصطلحات موضوعية: Control Engineering, Mechatronics and Robotics, Engineering, Biomedical Engineering, Clinical Research, Human Genome, Arthritis, Biotechnology, Pain Research, Aging, Genetics, Chronic Pain, Osteoarthritis, 2.1 Biological and endogenous factors, Aetiology, Musculoskeletal, Humans, Osteoarthritis, Hip, Femoracetabular Impingement, Hip Joint, RNA, Transcriptome, Cartilage, Articular, Disease Progression, Sequence Analysis, RNA, bioinformatics, femoroacetabular impingement, hip osteoarthritis, mRNA sequencing, Clinical Sciences, Human Movement and Sports Sciences, Orthopedics, Biomedical engineering, Sports science and exercise

الوصف: Femoroacetabular impingement (FAI) has a strong clinical association with the development of hip osteoarthritis (OA); however, the pathobiological mechanisms underlying the transition from focal impingement to global joint degeneration remain poorly understood. The purpose of this study is to use whole-genome RNA sequencing to identify and subsequently validate differentially expressed genes (DEGs) in femoral head articular cartilage samples from patients with FAI and hip OA secondary to FAI. Thirty-seven patients were included in the study with whole-genome RNA sequencing performed on 10 gender-matched patients in the FAI and OA cohorts and the remaining specimens were used for validation analyses. We identified a total of 3531 DEGs between the FAI and OA cohorts with multiple targets for genes implicated in canonical OA pathways. Quantitative reverse transcription-polymerase chain reaction validation confirmed increased expression of FGF18 and WNT16 in the FAI samples, while there was increased expression of MMP13 and ADAMTS4 in the OA samples. Expression levels of FGF18 and WNT16 were also higher in FAI samples with mild cartilage damage compared to FAI samples with severe cartilage damage or OA cartilage. Our study further expands the knowledge regarding distinct genetic reprogramming in the cartilage between FAI and hip OA patients. We independently validated the results of the sequencing analysis and found increased expression of anabolic markers in patients with FAI and minimal histologic cartilage damage, suggesting that anabolic signaling may be increased in early FAI with a transition to catabolic and inflammatory gene expression as FAI progresses towards more severe hip OA. Clinical significance:Cam-type FAI has a strong clinical association with hip OA; however, the cellular pathophysiology of disease progression remains poorly understood. Several previous studies have demonstrated increased expression of inflammatory markers in FAI cartilage samples, suggesting the involvement of these inflammatory pathways in the disease progression. Our study further expands the knowledge regarding distinct genetic reprogramming in the cartilage between FAI and hip OA patients. In addition to differences in inflammatory gene expression, we also identified differential expression in multiple pathways involved in hip OA progression.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1fr123vvTest

المؤلفون: Bermudez, Beatriz, Brown, Kenna C, Vahidi, Ghazal, Ferreira Ruble, Ana C, Heveran, Chelsea M, Ackert-Bicknell, Cheryl L, Sherk, Vanessa D

المساهمون: National Institutes of Health, National Science Foundation

المصدر: JBMR Plus ; volume 8, issue 4 ; ISSN 2473-4039

الوصف: Western diets are becoming increasingly common around the world. Western diets have high omega 6 (ω-6) and omega 3 (ω-3) fatty acids and are linked to bone loss in humans and animals. Dietary fats are not created equal; therefore, it is vital to understand the effects of specific dietary fats on bone. We aimed to determine how altering the endogenous ratios of ω-6:ω-3 fatty acids impacts bone accrual, strength, and fracture toughness. To accomplish this, we used the Fat-1 transgenic mice, which carry a gene responsible for encoding a ω-3 fatty acid desaturase that converts ω-6 to ω-3 fatty acids. Male and female Fat-1 positive mice (Fat-1) and Fat-1 negative littermates (WT) were given either a high-fat diet (HFD) or low-fat diet (LFD) at 4 wk of age for 16 wk. The Fat-1 transgene reduced fracture toughness in males. Additionally, male BMD, measured from DXA, decreased over the diet duration for HFD mice. In males, neither HFD feeding nor the presence of the Fat-1 transgene impacted cortical geometry, trabecular architecture, or whole-bone flexural properties, as detected by main group effects. In females, Fat-1-LFD mice experienced increases in BMD compared to WT-LFD mice; however, cortical area, distal femur trabecular thickness, and cortical stiffness were reduced in Fat-1 mice compared to pooled WT controls. However, reductions in stiffness were caused by a decrease in bone size and were not driven by changes in material properties. Together, these results demonstrate that the endogenous ω-6:ω-3 fatty acid ratio influences bone material properties in a sex-dependent manner. In addition, Fat-1 mediated fatty acid conversion was not able to mitigate the adverse effects of HFD on bone strength and accrual.

الإتاحة: https://doi.org/10.1093/jbmrpl/ziad011Test
https://academic.oup.com/jbmrplus/article-pdf/8/4/ziad011/57424856/ziad011.pdfTest

المؤلفون: Foessl, Ines, Ackert-Bicknell, Cheryl L., Kague, Erika, Laskou, Faidra, Jakob, Franz, Karasik, David, Obermayer-Pietsch, Barbara

المصدر: Trends in Endocrinology & Metabolism ; ISSN 1043-2760

مصطلحات موضوعية: Endocrinology, Endocrinology, Diabetes and Metabolism

الإتاحة: https://doi.org/10.1016/j.tem.2024.01.004Test
https://api.elsevier.com/content/article/PII:S1043276024000183?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1043276024000183?httpAccept=text/plainTest

المؤلفون: Wu, Euphy Y., Singh, Noor P., Choi, Kwangbom, Zakeri, Mohsen, Vincent, Matthew, Churchill, Gary A., Ackert-Bicknell, Cheryl L., Patro, Rob, Love, Michael I.

المساهمون: National Human Genome Research Institute, National Science Foundation, Division of Cancer Prevention, National Cancer Institute, National Institute of General Medical Sciences

المصدر: Genome Biology ; volume 24, issue 1 ; ISSN 1474-760X

الوصف: Detecting allelic imbalance at the isoform level requires accounting for inferential uncertainty, caused by multi-mapping of RNA-seq reads. Our proposed method, SEESAW, uses Salmon and Swish to offer analysis at various levels of resolution, including gene, isoform, and aggregating isoforms to groups by transcription start site. The aggregation strategies strengthen the signal for transcripts with high uncertainty. The SEESAW suite of methods is shown to have higher power than other allelic imbalance methods when there is isoform-level allelic imbalance. We also introduce a new test for detecting imbalance that varies across a covariate, such as time.

الإتاحة: https://doi.org/10.1186/s13059-023-03003-xTest

المؤلفون: Ackert-Bicknell, Cheryl L.

المساهمون: National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases

المصدر: Cell Genomics ; volume 3, issue 5, page 100325 ; ISSN 2666-979X

مصطلحات موضوعية: Genetics, Biochemistry, Genetics and Molecular Biology (miscellaneous)

الإتاحة: https://doi.org/10.1016/j.xgen.2023.100325Test
https://api.elsevier.com/content/article/PII:S2666979X23000939?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2666979X23000939?httpAccept=text/plainTest

المؤلفون: Medina-Gomez, Carolina, Kemp, John P, Trajanoska, Katerina, Luan, Jian’an, Chesi, Alessandra, Ahluwalia, Tarunveer S, Mook-Kanamori, Dennis O, Ham, Annelies, Hartwig, Fernando P, Evans, Daniel S, Joro, Raimo, Nedeljkovic, Ivana, Zheng, Hou-Feng, Zhu, Kun, Atalay, Mustafa, Liu, Ching-Ti, Nethander, Maria, Broer, Linda, Porleifsson, Gudmar, Mullin, Benjamin H, Handelman, Samuel K, Nalls, Mike A, Jessen, Leon E, Heppe, Denise HM, Richards, J Brent, Wang, Carol, Chawes, Bo, Schraut, Katharina E, Amin, Najaf, Wareham, Nick, Karasik, David, Van der Velde, Nathalie, Ikram, M Arfan, Zemel, Babette S, Zhou, Yanhua, Carlsson, Christian J, Liu, Yongmei, McGuigan, Fiona E, Boer, Cindy G, Bønnelykke, Klaus, Ralston, Stuart H, Robbins, John A, Walsh, John P, Zillikens, M Carola, Langenberg, Claudia, Li-Gao, Ruifang, Williams, Frances MK, Harris, Tamara B, Akesson, Kristina, Jackson, Rebecca D, Sigurdsson, Gunnar, Heijer, Martin den, van der Eerden, Bram CJ, van de Peppel, Jeroen, Spector, Timothy D, Pennell, Craig, Horta, Bernardo L, Felix, Janine F, Zhao, Jing Hua, Wilson, Scott G, de Mutsert, Renée, Bisgaard, Hans, Styrkársdóttir, Unnur, Jaddoe, Vincent W, Orwoll, Eric, Lakka, Timo A, Scott, Robert, Grant, Struan FA, Lorentzon, Mattias, van Duijn, Cornelia M, Wilson, James F, Stefansson, Kari, Psaty, Bruce M, Kiel, Douglas P, Ohlsson, Claes, Ntzani, Evangelia, van Wijnen, Andre J, Forgetta, Vincenzo, Ghanbari, Mohsen, Logan, John G, Williams, Graham R, Bassett, JH Duncan, Croucher, Peter I, Evangelou, Evangelos, Uitterlinden, Andre G, Ackert-Bicknell, Cheryl L, Tobias, Jonathan H, Evans, David M, Rivadeneira, Fernando

المصدر: American Journal of Human Genetics. 102(1)

مصطلحات موضوعية: Rare Diseases, Aging, Human Genome, Osteoporosis, Clinical Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Musculoskeletal, Good Health and Well Being, Adolescent, Age Factors, Animals, Bone Density, Child, Child, Preschool, Genetic Loci, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Mice, Knockout, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Regression Analysis, BMD, CREB3L1, ESR1, GWASs, RANKL, age-dependent effects, bone mineral density, fracture, genetic correlation, genome-wide association studies, meta-regression, total-body DXA, Biological Sciences, Medical and Health Sciences, Genetics & Heredity

الوصف: Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4tj3d2vrTest

المؤلفون: Nielson, Carrie M, Liu, Ching‐Ti, Smith, Albert V, Ackert‐Bicknell, Cheryl L, Reppe, Sjur, Jakobsdottir, Johanna, Wassel, Christina, Register, Thomas C, Oei, Ling, Alonso, Nerea, Oei, Edwin H, Parimi, Neeta, Samelson, Elizabeth J, Nalls, Mike A, Zmuda, Joseph, Lang, Thomas, Bouxsein, Mary, Latourelle, Jeanne, Claussnitzer, Melina, Siggeirsdottir, Kristin, Srikanth, Priya, Lorentzen, Erik, Vandenput, Liesbeth, Langefeld, Carl, Raffield, Laura, Terry, Greg, Cox, Amanda J, Allison, Matthew A, Criqui, Michael H, Bowden, Don, Ikram, M Arfan, Mellström, Dan, Karlsson, Magnus K, Carr, John, Budoff, Matthew, Phillips, Caroline, Cupples, L Adrienne, Chou, Wen‐Chi, Myers, Richard H, Ralston, Stuart H, Gautvik, Kaare M, Cawthon, Peggy M, Cummings, Steven, Karasik, David, Rivadeneira, Fernando, Gudnason, Vilmundur, Orwoll, Eric S, Harris, Tamara B, Ohlsson, Claes, Kiel, Douglas P, Hsu, Yi‐Hsiang

المصدر: Journal of Bone and Mineral Research. 31(12)

مصطلحات موضوعية: Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Human Genome, Aging, Osteoporosis, Biomedical Imaging, Aetiology, 2.1 Biological and endogenous factors, Musculoskeletal, Animals, Biopsy, Bone Density, Cancellous Bone, Excitatory Amino Acid Transporter 1, Gene Expression Regulation, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Linkage Disequilibrium, Lumbar Vertebrae, Mice, Molecular Sequence Annotation, Organ Size, Osteoblasts, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Receptor, EphB2, Risk Factors, Spinal Fractures, Spine, BONE QCT, CT, ANALYSIS, QUANTITATION OF BONE, OSTEOPOROSIS, DISEASES AND DISORDERS OF, RELATED TO BONE, GENERAL POPULATION STUDIES, EPIDEMIOLOGY, HUMAN ASSOCIATION STUDIES, GENETIC RESEARCH, FRACTURE RISK ASSESSMENT, ANALYSIS/QUANTITATION OF BONE, BONE QCT/μCT, DISEASES AND DISORDERS OF/RELATED TO BONE, EPIDEMIOLOGY, HUMAN ASSOCIATION STUDIES, Engineering, Medical and Health Sciences, Anatomy & Morphology, Biological sciences, Biomedical and clinical sciences

الوصف: Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF] = 3%) was associated with higher vBMD (β = 0.22, p = 1.9 × 10-8 ) and decreased risk of radiographic vertebral fracture (odds ratio [OR] = 0.75; false discovery rate [FDR] p = 0.01). In 1p36.12, rs12742784 (MAF = 21%) was associated with higher vBMD (β = 0.09, p = 1.2 × 10-10 ) and decreased risk of clinical vertebral fracture (OR = 0.82; FDR p = 7.4 × 10-4 ). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (β = 0.28, FDR p = 0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (β = 0.12, FDR p = 1.7 × 10-3 , functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence. © 2016 American Society for Bone and Mineral Research.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2h5496n5Test
https://escholarship.org/content/qt2h5496n5/qt2h5496n5.pdfTest

المؤلفون: Parker, Clarissa C, Gopalakrishnan, Shyam, Carbonetto, Peter, Gonzales, Natalia M, Leung, Emily, Park, Yeonhee J, Aryee, Emmanuel, Davis, Joe, Blizard, David A, Ackert-Bicknell, Cheryl L, Lionikas, Arimantas, Pritchard, Jonathan K, Palmer, Abraham A

المصدر: Nature Genetics. 48(8)

مصطلحات موضوعية: Biological Sciences, Genetics, Human Genome, Biotechnology, Behavioral and Social Science, Animals, Animals, Outbred Strains, Behavior, Animal, Brain, Gene Expression Regulation, Genetic Markers, Genome-Wide Association Study, Genotype, Mice, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology

الوصف: Although mice are the most widely used mammalian model organism, genetic studies have suffered from limited mapping resolution due to extensive linkage disequilibrium (LD) that is characteristic of crosses among inbred strains. Carworth Farms White (CFW) mice are a commercially available outbred mouse population that exhibit rapid LD decay in comparison to other available mouse populations. We performed a genome-wide association study (GWAS) of behavioral, physiological and gene expression phenotypes using 1,200 male CFW mice. We used genotyping by sequencing (GBS) to obtain genotypes at 92,734 SNPs. We also measured gene expression using RNA sequencing in three brain regions. Our study identified numerous behavioral, physiological and expression quantitative trait loci (QTLs). We integrated the behavioral QTL and eQTL results to implicate specific genes, including Azi2 in sensitivity to methamphetamine and Zmynd11 in anxiety-like behavior. The combination of CFW mice, GBS and RNA sequencing constitutes a powerful approach to GWAS in mice.

الوصول الحر: https://escholarship.org/uc/item/03r8k1ctTest

المؤلفون: Hamati, Mary C., Maynard, Robert, Bartolomei, Jonathan, Zuscik, Michael J., Ackert-Bicknell, Cheryl L., Hunt, Kenneth J.

المصدر: Foot & Ankle Orthopaedics ; volume 7, issue 1, page 2473011421S0022 ; ISSN 2473-0114 2473-0114

الوصف: Category: Ankle; Ankle Arthritis; Basic Sciences/Biologics; Trauma Introduction/Purpose: Osteoarthritis (OA) of the lower limb is a debilitating, incurable, expensive and prevalent condition in people over 45. Although ankle posttraumatic OA (PTOA) has the highest incidence, primary OA is increasingly recognized. The difference in OA incidence between lower limb joints is partly driven by differences in cartilage architecture and chondrocyte function at each site, with ankle chondrocytes showing reduced responsiveness to inflammatory mediators and more metabolic activity than those in the knee. Synovium also contributes to the pathogenesis of OA, however its potentially differential role in knee versus ankle OA remains an unanswered question. We aim to understand the molecular contribution of synovial dysregulation in the progression of ankle and knee OA to uncover candidate pathways for the development of targeted therapeutic paradigms. Methods: After obtaining informed consent from patients undergoing total knee or ankle replacement, basic surgical, past medical history, and imaging data was collected. Synovium samples were harvested during surgery and processed for RNA. Bulk 150 bp, paired-end RNA seq was conducted using standard protocols using the Illumina NovaSeq6000 platform. After quality control trimming, reads were aligned to human reference genome (GRCh38) using STAR (v 2.5) using the Maximum Mappable Prefix method and HTSeq (V0.6.1) was used to index mappable reads per gene. Counts were corrected for gene length using the FPKM method. Differential expression was determined using the edgeR (v 3.16.5) package for R, after adjustment using a scaling normalization factor and P-values were corrected using the Benjamini and Hochberg method. Similarities between samples were determined using Spearman Correlation and degree of similarity was visualized considering the first three Principal Components (PC). Results: RNA was obtained from 6 end-stage ankle OA, 1 end-stage knee OA patients. Of the ankle ...

الإتاحة: https://doi.org/10.1177/2473011421s00224Test

المؤلفون: Buckley, Sara E., Hamati, Mary C., Hewitt, Michael A., Ackert-Bicknell, Cheryl L., Zuscik, Michael J., Metzl, Joshua A., Moon, Daniel K., Hunt, Kenneth J.

المصدر: Foot & Ankle Orthopaedics ; volume 7, issue 4, page 2473011421S0060 ; ISSN 2473-0114 2473-0114

مصطلحات موضوعية: Orthopedics and Sports Medicine

الوصف: Category: Ankle Arthritis; Arthroscopy; Basic Sciences/Biologics; Trauma Introduction/Purpose: Post-traumatic Osteoarthritis (OA) of the ankle is a debilitating condition that impacts millions of people. However, little is known about the genetic and epigenetic risk factors for progression to OA following injury. In order to better understand these factors, a thorough knowledge of the molecular signature in ankle OA relative to non-arthritic ankles is critical. The objective of this study was to perform RNA-sequencing of ankle joint synovial samples from OA and non-OA ankles to better characterize the synovial transcriptome. We compared synovial gene expression patterns in patients with end-stage OA with ankle synovium from non-OA ankles to investigate the unique biological pathways altered in ankle OA. Methods: Patients undergoing total ankle arthroplasty or ankle arthrodesis for end stage OA and patients undergoing ankle arthroscopic surgery for non-arthritic conditions (negative control), were consented for participation. Patients with immune disorders or inflammatory arthropathies were excluded. Patient demographics and medical history were collected. Synovial samples were harvested during surgery and RNA was isolated. Bulk 150 bp, paired-end RNA seq was performed using the Illumina NovaSeq6000 platform. Differential expression was determined using the edgeR (v3.16.5) package for R, after adjustment using a scaling normalization factor and P-values were corrected using the Benjamini Hochberg method. Similarities between samples were determined using Spearman Correlation and degree of similarity was visualized considering the first three Principal Components. Gene Ontology terms were identified to classify gene properties. Results: A total of 8 synovial samples from total ankle OA and 24 synovial samples from ankle non-OA were available for analysis. We found 808 genes uniquely expressed in OA synovium and another 786 different genes expressed in synovium from the control group. GO enrichment term analysis ...

الإتاحة: https://doi.org/10.1177/2473011421s00600Test