Osteoarthritis (OA) is the most common form of arthritis and affects more than half of people over the age of 65 in the US. It is the most common cause of disability in our country, and the only definitive treatment for knee OA, joint replacement, is the #1 expense for Medicare each year. Despite all this, we have no medications that can slow or stop OA progression, nor do we have biomarkers to predict OA development or progression.
Unlike some other forms of arthritis, relatively few specific genetic associations have been found in OA. It seems that non-genetic, environmental factors play the biggest role in development and progression, including aging, obesity, and previous joint trauma. My laboratory is dedicated to figuring out how these non-genetic factors affect the way that cells within joints and in the immune system through epigenetic modifications. Epigenetics, meaning literally “above the gene”, are mechanisms that turn genes on and off without affecting the actual genetic code, usually by adding bits of chemical signals to DNA and other DNA-associated factors.
We hope to unravel the ways in which each particular OA risk factor affects the epigenetic state of genes in multiple types of cells throughout the body in an effort to help combat this disease. We are also focusing on interventions that might “fix” these epigenetic aberrations, including through modifying the microbiome, in hopes that we might be able to prevent OA or limit its severity.
Identifying epigenetic changes associated with OA in a variety of tissues: We have previously described differential DNA methylation within OA chondrocytes and subchondral bone in specimens from end-stage OA patients. My laboratory is now focused on determining, using mouse models of OA, which genes and/or gene pathways are epigenetically modified by individual OA risk factors including trauma, advanced age, and obesity induced by high-fat diet. We hope to better define which epigenetic aberrations are potentially “reversible”, i.e. associated with diet and obesity, and which are “non-reversible”, i.e. associated with aging and prior trauma.
Using epigenetics as clinical biomarkers for OA prediction: In a pilot project based on samples from the Osteoarthritis Initiative (OAI), we demonstrated the potential to use peripheral blood mononuclear cell (PBMC) DNA methylation-based models to distinguish knee OA patients who would go on to experience rapid radiographic progression within 24 months from patients who would not progress. Building on these findings, we are now evaluating PBMC DNA methylation patterns from a large set of OAI patients based on the Foundation for the NIH (FNIH) Osteoarthritis Biomarkers Consortium to determine whether models can be developed to differentiate nonprogressors from radiographic progressors from pain progressors, and radiographic and pain progressors from each of these groups.
The microbiome and OA: A distinguishing feature of the two risk factors most strongly associated with OA, aging and obesity, is that they both are associated with changes in the gut microbiome. We are investigating the ways in which these microbiome changes affect OA progression via modulation of the immune system. We are also interested in studying how the microbiome of OA-protected mice differ from OA-susceptible mice, and whether modification of the microbiome might have a beneficial effect in reducing OA pathology.
Cartilage microbial DNA and OA: In 2019, we made a pivotal discovery in finding traces of microbial DNA within human and mouse cartilage. Moreover, we found that microbial DNA patterns from human OA patients differed from disease-free human samples, and these differences were mirrored in cartilage from OA-susceptible compared to OA-resistant mice. We are now working to determine the source of this microbial DNA signature as well as investigating its role, if any, in OA pathogenesis.
B.S., biochemistry, University of Oklahoma, Norman, OK, 2005
M.D., University of Oklahoma Health Sciences Center, Oklahoma City, OK, 2010
Resident Physician, OUHSC Department of Internal Medicine, Oklahoma City, OK 2010-2013
Chief Resident, OUHSC Department of Internal Medicine, Oklahoma City, OK 2013–2014
Rheumatology Fellow, OUHSC Department of Rheumatology, Immunology, and Allergy, Oklahoma City, OK 2014–2016
Honors and Awards
2000-4 Oklahoma State Regents for Higher Education Academic Scholars Program, Oklahoma State University and University of Oklahoma
2006 Graduate Research Education and Technology Symposium Research Presentation Winner, OUHSC
2007 Clinical and Transitional Science Award and Preceptorship, OUHSC
2008 Special Recognition, Resident and Student Abstract Competition, American College of Rheumatology Research Workshop
2008 Abbott Medical Student Research Preceptorship, Rheumatology Education Foundation/Association of Rheumatologic Health Professionals
2009 Tinsley Harrison Award for best original research manuscript published in 2009, coauthor, American Journal of the Medical Sciences
2011 Joseph E. Johnson Leadership Day Award, American College of Physicians Leadership Day, Washington, D.C.
2012 James F. Hammarsten Award, Best Oral Research Presentation, OUHSC Stewart Wolf Research Forum
2012 Ephraim P. Engleman Endowed Resident Research Preceptorship, Rheumatology Education Foundation/Association of Rheumatologic Health Professionals
2012 Department of Internal Medicine Medical Student Teaching Award, OUHSC
2014 Lloyd Rader Resident Award for Excellence in Clinical Practice and Medical Research, OUHSC
2016 Invited guest speaker, Inaugural Epigenetics of Osteoarthritis Meeting, Amsterdam
2016 Distinguished Fellow Award, American College of Rheumatology
2018 Junior Faculty Research Award, Plenary Speaker, Southern Society for Clinical Investigation/American Federation for Medical Research
2018 Arthritis National Research Foundation Scholar
2019 Invited Year-In-Review speaker, Osteoarthritis Genetics and Epigenetics, Osteoarthritis Research Society International Annual Meeting in Liverpool
2019 Arthritis Foundation Oklahoma Chapter 2019 Professional Honoree
2019 Session Chair, Osteoarthritis Genetics and Epigenetics, Osteoarthritis Research Society International Annual Meeting in Toronto
2019 Provost’s Junior Faculty Research Award, OUHSC
American College of Rheumatology
American College of Physicians
Osteoarthritis Research Society International
Southern Society for Clinical Investigation
Joined OMRF Scientific Staff in 2020
Dunn CM, Velasco C, Rivas A, Andrews M, Garman C, Jacob PB, Jeffries MA. Identification of Cartilage Microbial DNA Signatures and Associations With Knee and Hip Osteoarthritis. Arthritis Rheumatol 72:1111-1122, 2020 July, PMID: 31961065, PMCID: PMC7336391
Jeffries MA. The Development of Epigenetics in the Study of Disease Pathogenesis. Adv Exp Med Biol 1253:57-94, 2020 January, PMID: 32445091
Dunn CM, Velasco C, Rivas A, Andrews M, Garman C, Jacob PB, Jeffries, MA. Identification of cartilage microbial DNA signatures and associations with knee and hip osteoarthritis. Arthritis Rheumatol. 2020 Jul;72(7):1111-1122. Epub 2020 May 12. PMID: 31961065, PMCID: PMC7336391 (available on 2021-07-01)
Dunn CM, Nevitt MC, Lynch JA, Jeffries MA. A pilot study of peripheral blood DNA methylation models as predictors of knee osteoarthritis radiographic progression: data from the Osteoarthritis Initiative (OAI). Sci Rep. 2019 Nov 14;9(1):16880. PMID: 31727952, PMCID: PMC6856188
Jeffries MA, Donica M, Baker L, Stevenson M, Annan AC, Humphrey MB, James JA, Sawalha AH. Genome-wide DNA methylation study identifies significant epigenomic changes in osteoarthritic subchondral bone and similarity to overlying cartilage. Arthritis Rheumatol. 2016 Jun;68(6):1403-14, PMID: 26713865 PMCID: PMC5484167
Jeffries MA, Donica M, Baker LW, Stevenson ME, Annan AC, Humphrey MB, James JA, Sawalha AH. Genome-wide DNA methylation study identifies significant epigenomic changes in osteoarthritic cartilage. Arthritis Rheumatol. 2014 Oct;66(10):2804-15. PMID: 24980887
Arthritis & Clinical Immunology Research Program, MS 53
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