Osteoarthritis (OA) is the most common musculoskeletal disease with an expected further increase in prevalence due to population aging. Although many drug targets have been identified and preclinical studies have shown efficacy in reducing disease severity, clinical trials on disease modifying OA drugs have failed. Experimental approaches such as testing disease-related differences in expression patterns of selected genes or proteins and analyzing function of these molecules in preclinical models has yielded a large number of pathways and molecules that are abnormally expressed or activated in OA. The limitations of these approaches are (i) that they provide only a selective and biased view of molecular changes that occur in OA and (ii) there has been no successful effort in integrating these findings into networks and prioritizing targets by their relevance as drivers of the OA process. This project leverages (i) our access to and expertise in working with human knee tissues from donors across the entire adult age spectrum and at all stages of OA development; (ii) human knee tissue libraries; (iii) technical advances in large scale, genome wide analyses of transcriptomes and epigenetic changes, which provide the opportunity to generate an unbiased and comprehensive view of the genetic landscape of cartilage homeostasis, aging and OA; (iv) our novel pipeline for integrative network analysis of multi-Omics data sets. Our hypothesis is that the gene expression and epigenetic (miRNA, other non-coding RNA, DNA methylation) data will generate novel signatures, pathways and key regulators of cartilage homeostasis, aging and OA.
Aim 1. Healthy cartilage aging: Identify novel transcriptomic and epigenomic (non-coding RNA and DNA methylation) markers of cartilage homeostasis and healthy aging.
Aim 2. OA-related changes: Reveal pathways and networks that are disrupted in OA and identify principal regulators of OA pathogenesis.
Aim 3. Validation: Confirm differences in gene and protein expression and analyze regulation and function of principal drivers of OA pathogenesis. Impact: To our knowledge, this is the first project to examine genome-wide mRNA expression profiles and genome-wide regulators of expression (miRs, other non-coding RNAs, DNA methylation) in cross-sectional healthy knee aging and OA. The proposed study has potential to lead to the discovery of (i) new biomarkers; (ii) novel pathways and principal molecular switches as therapeutic targets; and (iii) subsets of patients with unique epigenetic signatures and gene expression patterns, resulting in a personalized treatment approach. Ultimately this may lead to interventions to slow aging, and to the identification of therapeutic targets to delay or treat OA. By making the original data sets publicy available, the project will also generate a resource for the scientific community.

Public Health Relevance

This project will examine gene expression patterns and epigenetic mechanisms that characterize cartilage homeostasis, healthy aging and osteoarthritis using human knees. Data and insight generated from this proposal will provide new and important insights into the biology of aging and osteoarthritis, and may lead to new biomarkers, and identify more promising targets for therapeutic interventions to delay or treat osteoarthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG049617-03
Application #
9412775
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Williams, John
Project Start
2016-01-15
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Matsuzaki, Tokio; Alvarez-Garcia, Oscar; Mokuda, Sho et al. (2018) FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and osteoarthritis. Sci Transl Med 10:
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Yu, Xiaodan; Kawakami, Hiroko; Tahara, Naoyuki et al. (2017) Expression of Noggin and Gremlin1 and its implications in fine-tuning BMP activities in mouse cartilage tissues. J Orthop Res 35:1671-1682
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