Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability in older Americans;thus, OA poses an enormous social and economic burden in the US. OA progression is certain and since cartilage has limited regenerative capacity, total joint replacement is the only effective treatment for OA. Despite the high success rates of reducing pain and restoring mobility, joint implants have limited lifespans and surgeries present many risks, including infections. Thus, new strategies to promote articular cartilage repair and/or slow articular cartilage degeneration and disease progression are needed. The goal of this five year career development application is to establish a research program exploring the role of the protein phosphatase Phlpp1 in osteoarthritis disease (OA) progression and to explore the epigenetic mechanisms that control Phlpp1 transcription in OA. To date, the applicant's research experience focused mainly on cellular and genetic models that do not recapitulate the OA phenotype. The proposed research in this application will further advance the investigator's qualifications by providing training in surgical models of osteoarthriti and their characterization through functional assessments of pain, equilibrium partitioning of an ionic contrast agent via microcomputed tomography (EPIC-microCT), histological scoring and epigenetic/transcriptional control of gene expression. This training will provide a comprehensive skill set required for mechanistic studies detailing the ability of epigenetic factors to modulate OA progression. The completion of this project and the training received at the Mayo Clinic will prepare the Principal Investigator to be a leading contributor to the field of osteoarthritis-relatd research.

Public Health Relevance

Osteoarthritis (OA) is characterized by articular cartilage deterioration. OA is the most common form of arthritis and a leading cause of disability in older Americans. As the second most common reason for patients to visit a physician, OA poses an enormous social and economic burden in the US. Because of its limited regenerative capacity, articular cartilage is particularly challenging to repair. The best treatment options currently to repair OA damage and reduce pain are surgical interventions. Since surgeries pose many risks and implants have limited lifespans, new strategies to promote articular cartilage repair are needed. My project explores the role of a newly identified regulator of chondrocyte differentiation, Phlpp1, in the progression of osteoarthritis (OA) and during cartilage development. These studies will provide understanding of molecular events underlying the progression of OA.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Scientist Development Award - Research & Training (K01)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Tyree, Bernadette
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Mayo Clinic, Rochester
United States
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Hwang, Soyun M; Feigenson, Marina; Begun, Dana L et al. (2018) Phlpp inhibitors block pain and cartilage degradation associated with osteoarthritis. J Orthop Res 36:1487-1497
Camilleri, Emily T; Dudakovic, Amel; Riester, Scott M et al. (2018) Loss of histone methyltransferase Ezh2 stimulates an osteogenic transcriptional program in chondrocytes but does not affect cartilage development. J Biol Chem 293:19001-19011
Castillejo Becerra, Clara M; Mattson, Anna M; Molstad, David H H et al. (2018) DNA methylation and FoxO3a regulate PHLPP1 expression in chondrocytes. J Cell Biochem 119:7470-7478
Feigenson, Marina; Shull, Lomeli Carpio; Taylor, Earnest L et al. (2017) Histone Deacetylase 3 Deletion in Mesenchymal Progenitor Cells Hinders Long Bone Development. J Bone Miner Res 32:2453-2465
Xu, Ming; Bradley, Elizabeth W; Weivoda, Megan M et al. (2017) Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice. J Gerontol A Biol Sci Med Sci 72:780-785
Carpio, Lomeli R; Bradley, Elizabeth W; Westendorf, Jennifer J (2017) Histone deacetylase 3 suppresses Erk phosphorylation and matrix metalloproteinase (Mmp)-13 activity in chondrocytes. Connect Tissue Res 58:27-36
Carpio, Lomeli R; Bradley, Elizabeth W; McGee-Lawrence, Meghan E et al. (2016) Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling. Sci Signal 9:ra79
Fang, Dong; Gan, Haiyun; Lee, Jeong-Heon et al. (2016) The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. Science 352:1344-8
Bradley, E W; Carpio, L R; McGee-Lawrence, M E et al. (2016) Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis. Osteoarthritis Cartilage 24:1021-8
Bonin, Carolina A; Lewallen, Eric A; Baheti, Saurabh et al. (2016) Identification of differentially methylated regions in new genes associated with knee osteoarthritis. Gene 576:312-8

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