single reference image (atlas) which can be used to determine T1r and T2 in identical regions and statistical parameter maps, such as Z score maps.
Abstracts / Osteoarthritis and Cartilage 26 (2018) S1eS9
single reference image (atlas) which can be used to determine T1r and T2 in identical regions and statistical parameter maps, such as Z score maps (with respect to controls), t-tests between cohorts, regression with function, lesion scores. An example of the VBR technique are shown in Figure 1. Fig. 1A shows the color map for the average T1r for controls, which is similar across the femoral head, and 1B shows the map for an OA subject showing regions of increased relaxation time. The analysis of atlas-based voxel by voxel comparisons has shown significant association with patient functional scores (Fig. 1D). Significant positive association was seen between VBR z-score and the Timed Up and Go (TUG) test, which is a measure of patient mobility and speed. Subjects with local elevations of T1r in the central region of the acetabulum are associated with worse function at 18-month follow up. Using VBR we calculated the voxel-by-voxel differences in baseline T1r (t-test) between progressors and non-progressors (Fig. 2). Regions of significant differences (p < 0.05) are shown as highlighted and by white arrows. Femoro-acetabular impingement (FAI) has become a well-recognized pathogenic factor in the evolution of hip OA. We found T1r and T2 global acetabular values were significantly higher in FAI patients with a focal increase within the posterior acetabular cartilage. FAI patients exhibited increased anterior superior acetabular T1r and T2 heterogeneity and both of these measures demonstrated a strong ability to detect acetabular cartilage delamination. There has been a growing interest in the analysis of bone shape as an early knee and hip OA imaging biomarker, MRI has the potential to extract more detailed shape features, but challenges such as segmenting the bone and other tissues becomes time intensive if done manually, or even semi-automatically. Machine learning, deep learning based methodologies for segmentation will be reviewed and presented in this context. Specific bone shape features are associated with the presence of femoral and acetabular cartilage abnormalities and prolongation in T1r and T2 relaxation times, indicating changes in cartilage biochemistry consistent with the onset of OA. These shape variations are associated with hip joint mechanics. Given the multifactorial nature of OA, it is necessary to analyze all factors (i.e., morphological, compositional, and biomechanical) simultaneously. Multidimensional data analysis to discover new interactions between different aspects of the disease, will also be discussed. Conclusions: Advanced imaging methods have been introduced for the study of hip OA, and the next decade will see a major expansion on the understanding of cartilage degeneration, biomechanics and function.
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OA [1]. These technologies enable precise targeting of DNA to allow activation, suppression, or editing of specific genes for disease modeling and therapeutic purposes. While genome-wide association studies (GWAS) and genomics have provided new leads on the genetic basis for various forms of OA, validation and characterization of the causal variants at these loci will be a key challenge that is necessary for identification of therapeutic targets (Fig. 1). With recent advances in gene editing and genome engineering technologies, functional validation of genetic variation of regulatory elements and coding sequences in human cell types has become feasible. The generation of cell lines with targeted editing of susceptibility variants in an isogenic background can be accomplished using newly developed tools for genome/epigenome editing. The clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system has revolutionized the field of genome/epigenome editing by eliminating the need for protein engineering to obtain site specificity, thereby increasing accessibility to the platform. This presentation reviews some of the recent advances in CRISPR-Cas9-based genome editing, activation, inactivation, as well as epigenome editing. Applications of this method include: 1) development of cell-based systems for disease modeling as a basis for screening disease-modifying OA drugs (DMOADs); 2) targeted editing of the cellular genome for tissue engineering and regenerative medicine; 3) large-scale screening using libraries of CRISPR-based activators and inhibitors (CRISPRa/i) for identification/validation of genomic targets. Overall, there remains great opportunity to revolutionize the fields of OA research through application of these newly developed genome engineering tools. References 1. Adkar SS, Brunger JM, Willard VP, Wu CL, Gersbach CA, Guilak F. Genome engineering for personalized arthritis therapeutics. Trends Mol Med. 23(10):917e931, 2017.
I-22 TARGETING SECONDARY PREVENTION OF OSTEOARTHRITIS: WHO IS AT GREATEST RISK FOLLOWING JOINT INJURY? J.L. Whittaker y, z. y University of Alberta, Edmonton, AB, Canada; z Glen Sather Sports Medicine Clinic, Edmonton, AB, Canada I-20 DEBATE e CHONDROCYTES: BETTER DEAD OR ALIVE? M. Lotz y, M. Warman z. y The Scripps Research Institute, La Jolla, CA, USA; Children's Hospital Boston, Boston, MA, USA
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The debate will address mechanisms and patterns of cell death in cartilage during aging and osteoarthritis. The main point of discussion is whether cell death contributes to cartilage damage and osteoarthritis pathogenesis. The two opposing positions are that cell survival is not essential for maintenance of tissue integrity versus cell death contributes to tissue damage. I-21 TARGETED GENOME AND EPIGENOME EDITING FOR OA RESEARCH AND THERAPY F. Guilak. Washington University and Shriners Hospital for Children, St. Louis, MO, USA Osteoarthritis (OA) represents a family of complex and chronic joint pathologies that have few or no disease-modifying therapeutics available. Advances in genome engineering technology, most recently with CRISPR-Cas9, have revolutionized our ability to interrogate and validate genetic and epigenetic elements associated with chronic diseases such as
Background: Osteoarthritis (OA) is one of the fastest growing health condition burdens in terms of Years Lived with Disability. The forces driving this growth include an aging population, earlier onset, and lack of disease modifying treatments. Osteoarthritis is amenable to prevention, however before an upstream shift from treatment to prevention can occur, key knowledge gaps must be bridged. Specifically, early diagnostic markers to determine who will benefit from prevention efforts, modifiable risk factors, and protective mechanisms must be identified. Post-traumatic knee OA (PTOA) provides a unique opportunity to address these gaps as meta-analyses indicate increased odds of PTOA 10e15 years after a significant knee joint injury. Thus, monitoring key outcomes in the interval between joint injury and PTOA onset may provide clues vital to understanding early detection of PTOA, and modifiable risk/protective factors that can be targeted to prevent, or delay progression to PTOA. Purpose: The purpose of this presentation is to provide an overview of potential treatment targets/strategies for secondary prevention of PTOA based on a synthesis of investigations that have reported modifiable risk/protective factors amenable to intervention in the interval between joint injury and PTOA onset. A secondary aim is to discuss the need for international collaboration and consensus on early PTOA outcomes given that few studies have followed individuals across this entire interval, and even fewer have included a comparison to uninjured controls where key variables that may modify or confound the
