Ph.D., 2006 Yale University
Assistant Professor of Orthopaedics
Primary Appointment: Department of Orthopaedics
Center Affiliation: Center for Musuculoskeletal Research
Most of the bones of the vertebrate skeleton develop through a complex, multistep process known as endochondral ossification whereby bone formation occurs following the generation of a cartilage template. Specifically, during early embryonic development, condensations of mesenchymal progenitor cells differentiate into chondrocytes, the cells responsible for producing the cartilage matrix, and progress through a program of proliferation and maturation. For example, those chondrocytes most central to the cartilage template exit from the cell cycle and undergo hypertrophy secreting factors that promote mineralization, degradation, and vascular invasion of the cartilage matrix. Terminally mature chondrocytes then undergo apoptosis leaving behind the cartilage scaffold for bone matrix deposition and remodeling by infiltrating osteoblasts and osteoclasts, respectively. On either side of the newly formed bone, continued chondrocyte proliferation and maturation establish the growth plate cartilage driving longitudinal bone growth.
Postnatally, a second center of bone formation develops in the epiphyses of the limbs separating the growth plate cartilage from the developing articular cartilage. The articular cartilage is avascular, has a high matrix to cell volume ratio, and is divided into distinct zones based on biochemical composition. Unlike growth plate chondrocytes, the resident articular chondrocytes do not undergo a rapid maturation process leaving most of the cartilage matrix unmineralized and providing a surface that permits free movement of joints. Only under certain circumstances, such as in osteoarthritis (OA), do these chondrocytes undergo aberrant maturation resulting in mineralization of the cartilage matrix.
The Jonason laboratory is interested in the signaling mechanisms that govern mesenchymal stem cell differentiation as well as maturation of committed chondrocytes and osteoblasts during skeletal development. Additionally, we have a strong interest in those mechanisms that function to maintain articular chondrocytes and the integrity of the articular cartilage matrix. We combine in vivo genetic mouse models with in vitro tissue culture and molecular biology techniques to better understand the role of specific signaling pathways and transcription factors in regulation of bone and joint development as well as in the onset and progression of osteoarthritis.
Skeletal Development and Growth Plate Chondrocyte Maturation
Multiple growth factors and their intracellular signaling components have been identified as critical for the development of a normal skeleton. These pathways lead to the regulation of transcription factors necessary for lineage determination of mesenchymal stem cells and maturation of committed chondrocyte and osteoblast progenitors. We are particularly interested in the roles of the Wnt/β-catenin and Bmp/Tak1 signaling pathways during mesenchymal progenitor cell differentiation and growth plate chondrocyte maturation. Additionally, we are interested in how these pathways affect the expression and activity of chondro- and osteo-lineage-specific transcription factors, such as Sox9 and Runx2. The mouse provides an excellent model system for the study of skeletal development as the underlying processes involved are well conserved between mice and humans. Additionally, the mouse genome can be manipulated to allow deletion, mis-expression, or mutation of genes of interest. Using the mouse Cre-loxP system, we are able to delete or overexpress genes relevant to our pathways of interest in specific cell types of mesenchymal origin in order to determine their cell-autonomous and non-cell-autonomous contributions to the developmental process. We also employ defined in vitro tissue culture systems to investigate the molecular events downstream of Wnt/β-catenin and Bmp/Tak1 signaling throughout the various stages of chondrocyte maturation.
Articular Cartilage Homeostatis and Osteoarthritis
Osteoarthritis (OA) is a debilitating degenerative joint disease characterized by an irreversible loss of articular cartilage within the synovial joints. During the onset of OA, the articular chondrocytes responsible for production of the articular cartilage matrix undergo phenotypic changes similar to those that growth plate chondrocytes undergo during terminal maturation. While genetic, mechanic, and metabolic factors all contribute to the development of OA, we are primarily interested in the identification of genetic perturbations that give rise to the disease. Using genetic mouse models and articular chondrocyte cultures, we are actively investigating the role of several signaling pathways and transcription factors in articular cartilage maintenance and in the onset and progression of OA. Using a mouse meniscal/ligamentous injury (MLI) model of OA, we are also exploring the potential synergy between inflammatory and genetic factors on the rate and severity of OA progression.
Mesenchymal Stem Cell Self-renewal and Differentiation
Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the ability to differentiate into chondrocytes, osteoblasts, and adipocytes, depending on their environment and the combination of growth and differentiation factors received. MSCs are not only important during development, but also during the repair of injured postnatal and adult tissues. With increasing interest in the clinical use of MSCs for tissue repair, it is of critical importance to define the signaling pathways that regulate MSC self-renewal, proliferation, lineage commitment, and differentiation. In our lab, we are particularly interested in the regulation of MSC populations by the Wnt/β-catenin and Bmp/Tak1 signaling pathways. We culture primary MSCs isolated from mouse bone marrow and periosteum to study, in vitro, the signaling mechanisms governing MSC fate. Additionally, using the mouse Cre-loxP system, we are able to determine the in vivo role of genes of interest specifically in limb mesenchymal stem cells during skeletal development.
Gao L, Sheu TJ, Dong Y, Hoak DM, Zuscik MJ, Schwarz EM, Hilton MJ, O'Keefe RJ, Jonason JH. TAK1 regulates SOX9 expression in chondrocytes and is essential for postnatal development of the growth plate and articular cartilages. J Cell Sci. 2013; 126(24):5704-13. (Recommended by the “Faculty of 1000”).
Dao DY, Jonason JH, Zhang Y, Hsu W, Chen D, Hilton MJ, O’Keefe RJ. Cartilage-specific B-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development. J Bone Miner Res. 2012; 27(8):1680-94.
Metz-Estrella D, Jonason JH, Sheu T-J, Mroczek-Johnston RM, Puzas JE. TRIP-1, a regulator of osteoblast function. J Bone Miner Res. 2012; 27(7):1576-84.
Zhang M, Ho H-C, Sheu T-J, Breyer MD, Flick LM, Jonason JH, Awad HA, Schwarz EM, O’Keefe RJ. EP1-/- mice have enhanced osteoblast differentiation and accelerated fracture repair. J Bone Miner Res. 2011; 26(4):792-802.
Li T-F, Gao L, Sheu T-J, Sampson ER, Flick LM, Konttinen YT, Chen D, Schwarz EM, Zuscik MJ, Jonason JH, O’Keefe RJ. Aberrant hypertrophy in Smad3-deficient murine chondrocytes is rescued by restoring transforming growth factor beta-activated kinase 1/activating transcription factor 2 signaling: A potential clinical implication for osteoarthritis. Arthritis Rheum. 2010; 62(8):2359-69.
Gunnell LM, Jonason JH, Loiselle AE, Kohn A, Schwarz EM, Hilton MJ, O'Keefe RJ. TAK1 regulates cartilage and joint development via the MAPK and BMP signaling pathways. J Bone Miner Res. 2010; 25(8):1784-97.
Yan Y, Tang D, Chen M, Huang J, Xie R, Jonason JH, Tan X, Hou W, Reynolds D, Hsu W, Harris SE, Puzas JE, Awad H, O'Keefe RJ, Boyce BF, Chen D. Axin2 controls bone remodeling through the beta-catenin-BMP signaling pathway in adult mice. J Cell Sci. 2009; 122(19):3566-78.
Jonason JH, Xiao G, Zhang M, Xing L, Chen D. Post-translational regulation of Runx2 in bone and cartilage. J Dent Res. 2009; 88(8):693-703.
Zhang M, Xie R, Hou W, Wang B, Shen R, Wang X, Wang Q, Zhu T, Jonason JH, Chen D. PTHrP prevents chondrocyte premature hypertrophy by inducing cyclin-D1-dependent Runx2 and Runx3 phosphorylation, ubiquitylation and proteasomal degradation. J Cell Sci. 2009; 122(9):1382-9.
Jonason JH, Gavrilova N, Wu M, Zhang H, Sun H. Regulation of SCFSKP2 ubiquitin E3 ligase assembly and p27KIP1 proteolysis by the PTEN pathway and Cyclin D1. Cell Cycle. 2007; 6(8):951-61.
Hulit J, Lee RJ, Li Z, Wang C, Katiyar S, Yang J, Quong AA, Wu K, Albanese C, Russell R, Di Vizio D, Koff A, Thummala S, Zhang H, Harrell J, Sun H, Muller WJ, Inghirami G, Lisanti MP, Pestell RG. p27Kip1 repression of ErbB2-induced mammary tumor growth in transgenic mice involves Skp2 and Wnt/β-Catenin signaling. Cancer Res. 2006; 66(17):8529-41.
Zheng J, Yang X, Harrell JM, Ryzhikov S, Shim EH, Lykke-Andersen K, Wei N, Sun H, Kobayashi R, Zhang H. CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex. Mol Cell. 2002; 10(6):1519-26.
Graduate Program Affiliation
Jennifer Jonason, PhD
University of Rochester
601 Elmwood Ave., Box 665
Rochester, NY 14642
(585) 275-1121 (fax)