Osteoarthritis (OA) is a highly prevalent, disabling degenerative disease of the joints that is characterized by progressive deleterious changes in the articular cartilage, subchondral bone, and other joint tissues. This project will exploit emerging evidence from exome sequencing in a unique selection of (early onset) familial OA cases that resulted in the identification of high impact mutations in COL6A3 likely causal to OA. The mechanism by which such a mutation increases the risk for OA is unclear, partly because there is substantial genetic variation among the population and lifestyle differences that can affect the development of OA. We propose to develop a novel in vitro system for studying the functional effect of identified OA causal variants on the biochemical and mechanical properties of articular cartilage using genome editing of COL6A3 in induced pluripotent stem cells (iPSCs) and cartilage tissue engineering. Type VI collagen plays a critical role in the function of the chondron ? the chondrocyte and its surrounding pericellular matrix ? which has been shown the regulate the biological and biomechanical environment of chondrocytes in articular cartilage. We will use a combined experimental and theoretical modeling approach to determine how changes in the physicochemical properties of the PCM with COL6A3 mutation influence the mechanical interactions between the chondrocyte and ECM in chondrogenically differentiated iPSCs. We will examine the early signaling events as well as the long-term influence of COL6A3 knockout or mutation on chondrocyte response to loading. Finally, we will examine the effect of the COL6A3 knockout or mutation on the epigenetically controlled changes of the transcriptome of chondrocytes in response to loading. A detailed understanding of these mechanisms will provide critical insight into the development of new pharmacologic, regenerative, or physical therapies for OA.
Chondrocytes, the cells in articular cartilage, are surrounded by a pericellular matrix that is rich in type VI collagen. We have identified high impact mutations in the gene COL6A3 as a risk factor for osteoarthritis. Here we will examine how these mutations influence the complex interplay between the chondrocyte, its pericellular matrix, and the extracellular matrix in regulating articular cartilage tissue homeostasis in health and disease. This information will hopefully lead to novel pharmacologic targets for osteoarthritis.
|Guilak, Farshid; Nims, Robert J; Dicks, Amanda et al. (2018) Osteoarthritis as a disease of the cartilage pericellular matrix. Matrix Biol 71-72:40-50|
|Rowland, Christopher R; Glass, Katherine A; Ettyreddy, Adarsh R et al. (2018) Regulation of decellularized tissue remodeling via scaffold-mediated lentiviral delivery in anatomically-shaped osteochondral constructs. Biomaterials 177:161-175|
|Furman, Bridgette D; Kent, Collin L; Huebner, Janet L et al. (2018) CXCL10 is upregulated in synovium and cartilage following articular fracture. J Orthop Res 36:1220-1227|
|Tang, Ruhang; Jing, Liufang; Willard, Vincent P et al. (2018) Differentiation of human induced pluripotent stem cells into nucleus pulposus-like cells. Stem Cell Res Ther 9:61|
|Erdemir, Ahmet; Hunter, Peter J; Holzapfel, Gerhard A et al. (2018) Perspectives on Sharing Models and Related Resources in Computational Biomechanics Research. J Biomech Eng 140:|
|Adkar, Shaunak S; Brunger, Jonathan M; Willard, Vincent P et al. (2017) Genome Engineering for Personalized Arthritis Therapeutics. Trends Mol Med 23:917-931|
|Liu, Betty; Goode, Adam P; Carter, Teralyn E et al. (2017) Matrix metalloproteinase activity and prostaglandin E2 are elevated in the synovial fluid of meniscus tear patients. Connect Tissue Res 58:305-316|
|Wu, Chia-Lung; Kimmerling, Kelly A; Little, Dianne et al. (2017) Serum and synovial fluid lipidomic profiles predict obesity-associated osteoarthritis, synovitis, and wound repair. Sci Rep 7:44315|
|Brunger, Jonathan M; Zutshi, Ananya; Willard, Vincent P et al. (2017) CRISPR/Cas9 Editing of Murine Induced Pluripotent Stem Cells for Engineering Inflammation-Resistant Tissues. Arthritis Rheumatol 69:1111-1121|
|Wu, Chia-Lung; McNeill, Jenna; Goon, Kelsey et al. (2017) Conditional Macrophage Depletion Increases Inflammation and Does Not Inhibit the Development of Osteoarthritis in Obese Macrophage Fas-Induced Apoptosis-Transgenic Mice. Arthritis Rheumatol 69:1772-1783|
Showing the most recent 10 out of 229 publications