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Jonason Lab

Jennifer Jonason

Ph.D., 2006 Yale University

Research Associate Professor of Orthopaedics

Primary Appointment: Department of Orthopaedics

Center Affiliation: Center for Musculoskeletal Research

Research Overview

Osteoarthritis, or OA, is a debilitating degenerative joint disease characterized by an irreversible loss of articular cartilage within the synovial joints. The primary research goal of the Jonason laboratory is to better define the molecular mechanisms leading to the onset and progression of OA with age or following traumatic joint injury. In particular, we are interested in the roles of both acute and chronic local inflammation in OA pathogenesis and the effects of this inflammation on chondrocyte fate and cartilage metabolism. Additionally, we study mechanisms that govern chondrocyte proliferation and maturation, processes relevant to OA as well as to skeletal development and repair. We combine in vivo genetic mouse models with in vitro tissue culture and molecular biology techniques to better understand the roles of specific signaling pathways in regulation of these processes with the hope of identifying novel therapeutic targets to promote cartilage regeneration or inhibit OA disease progression.

Research Programs

Articular Cartilage Homeostasis and Osteoarthritis

OAArticular cartilage is avascular, non-innervated, 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 rapidly proliferate or undergo hypertrophy leaving most of the cartilage matrix unmineralized and providing a surface that permits free movement of joints. Only under pathologic conditions, such as in OA, do these chondrocytes undergo aberrant proliferation and maturation resulting in degeneration and mineralization of the cartilage matrix. In general, we are interested in the molecular mechanisms that function to maintain articular chondrocytes in a non-proliferative, non-hypertrophic state. We are equally interested in the molecular events that occur with aging or joint injury to promote aberrant chondrocyte proliferation and maturation, likely initiating the onset of OA. We are actively investigating the role of several signaling pathways and transcription factors in articular cartilage maintenance and in OA pathogenesis using novel genetic mouse models as well as mouse models of aging and meniscal/ligamentous injury (MLI). Ongoing areas of investigation are further described below.

Inflammation and OA

InflammationInflammation is increasingly accepted as a key participant in the pathogenesis of OA. Whether the inflammation detected in osteoarthritic joints is responsible for initiating the onset of disease or simply promoting disease progression, however, remains unclear. We are particularly interested in the role of IKKß/NF-kB signaling as a source of chronic inflammation in aging joints and find that chondrocyte-specific activation of this pathway can accelerate the onset of age-associated OA. Our current studies focus on investigating both the downstream effects and upstream sources of IKKß/NF-kB activation in aging joint tissues. Additionally, we are exploring the potential synergy between inflammatory and genetic factors on the rate and severity of OA progression following joint injury. ​

TAK1 Signaling and OA

Tak1We have found that chondrocyte-specific TAK1 signaling is essential for normal development of the articular cartilage in early postnatal life. TAK1 is a MAP3K involved in non-canonical BMP and TGF-ß signaling as well as in activation of canonical IKKß/NF-kB signaling downstream of several pro-inflammatory cytokines. Thus, we are currently investigating the roles of TAK1 in articular cartilage homeostasis during aging and in OA pathogenesis following traumatic joint injury.

Mitochondrial Dysfunction and OA

MitochondrialMitochondrial dysfunction plays a causative role in a number of degenerative processes, however, the relationship between mitochondrial dysfunction and OA is currently unclear. The most common mechanism leading to mitochondrial dysfunction is opening of the mitochondrial permeability transition pore (MPTP). The MPTP is located within the inner mitochondrial membrane and gated by Cyclophilin D (CypD). MPTP opening can occur following traumatic tissue injury. In collaboration with Dr. Roman Eliseev’s lab, we are currently investigating the effects of CypD loss or constitutive activation in articular chondrocyte fate and OA development following traumatic joint injury.

Skeletal Development and Growth Plate Chondrocyte Maturation

DevelopmentMultiple 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 non-canonical BMP and TGF-ß signaling via TAK1 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. 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.

Selected Publications

  • Catheline SE, Hoak D, Chang M, Ketz JP, Hilton MJ, Zuscik MJ, Jonason JH. Chondrocyte-specific RUNX2 overexpression accelerates post-traumatic osteoarthritis progression in adult mice. J Bone Miner Res. In press.
  • Feigenson M, Jonason JH, Shen J, Loiselle AE, Awad HA, O'Keefe RJ. Inhibition of the Prostaglandin EP-1 Receptor in Periosteum Progenitor Cells Enhances Osteoblast Differentiation and Fracture Repair. Ann Biomed Eng. 2019; Apr 12 (ePub).
  • Yukata K, Xie C, Li TF, Brown ML, Kanchiku T, Zhang X, Awad HA, Schwarz EM, Beck CA, Jonason JH*, O'Keefe RJ*.  Teriparatide (human PTH1-34) compensates for impaired fracture healing in COX-2 deficient mice.  Bone. 2018; 110:150-159.
  • MacLauchlan S, Zuriaga A, Fuster JJ, Cuda CM, Jonason J, Behzadi F, Duffen JP, Haines GK 3rd, Aprahamian T, Perlman H, Walsh K.  Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis.  Arthritis Res Ther. 2017; 19(1): 166.
  • Feigenson M, Eliseev RA, Jonason JH, Mills BN, O'Keefe RJ.  PGE2 Receptor Subtype 1 (EP1) Regulates Mesenchymal Stromal Cell Osteogenic Differentiation by Modulating Cellular Energy Metabolism.  J Cell Biochem. 2017; 118(12): 4383-4393.
  • Ackerman JE, Bah I, Jonason JH, Buckley MR, Loiselle AE.  Aging does not alter tendon mechanical properties during homeostasis, but does impair flexor tendon healing.  J Orthop Res.  2017; 35(12): 2716-2724.
  • Dar QA, Schott EM, Catheline SE, Maynard RD, Liu Z, Kamal F, Farnsworth CW, Ketz JP, Mooney RA, Hilton MJ, Jonason JH, Prawitt J, Zuscik MJ.  Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis.  PLoS One.  2017; 12(4): e0174705.
  • Zhang Y, O'Keefe RJ, Jonason JH.  BMP-TAK1 (MAP3K7) induces adipocyte differentiation through PPARγ signaling.  J Cell Biochem.  2017; 118(1): 204-210.
  • Shum LC, White NS, Nadtochiy SM, Bentley KL, Brookes PS, Jonason JH, Eliseev RA. Cyclophilin D knock-out mice show enhanced resistance to osteoporosis and to metabolic changes observed in aging bone.  PLoS One.  2016; 11(5): e0155709.
  • Hamada D, Maynard R, Schott E, Drinkwater CJ, Ketz JP, Kates SL, Jonason JH, Hilton MJ, Zuscik MJ, Mooney RA.  Suppressive effects of insulin on Tumor Necrosis Factor-dependent early osteoarthritic changes associated with obesity and Type 2 Diabetes Mellitus.  Arthritis Rheumatol.  2016; 68(6): 1392-402.
  • Zhang Y, Sheu TJ, Hoak D, Shen J, Hilton MJ, Zuscik MJ, Jonason JH*, O'Keefe RJ*.  CCN1 regulates chondrocyte maturation and cartilage development.  J Bone Miner Res.  2016; 31(3): 549-59.
  • Loiselle AE, Yukata K, Geary MB, Kondabolu S, Shi S, Jonason JH, Awad HA, O'Keefe RJ.  Development of antisense oligonucleotide (ASO) technology against Tgf-β signaling to prevent scarring during flexor tendon repair.  J Orthop Res.  2015; 33(6): 859-66.
  • Zhang M, Feigenson M, Sheu TJ, Awad HA, Schwarz EM, Jonason JH, Loiselle AE, O'Keefe RJ.  Loss of the PGE2 receptor EP1 enhances bone acquisition, which protects against age and ovariectomy-induced impairments in bone strength.  Bone.  2015; 72:92-100.
  • Jonason JH, Hoak D, O'Keefe RJ.  Primary murine growth plate and articular chondrocyte isolation and cell culture.  Methods Mol Biol.  2015; 1226: 11-18.
  • Yukata K, Xie C, Li TF, Takahata M, Hoak D, Kondabolu S, Zhang X, Awad HA, Schwarz EM, Beck CA, Jonason JH, O'Keefe RJ.  Aging periosteal progenitor cells have reduced regenerative responsiveness to bone injury and to the anabolic actions of PTH 1-34 treatment.  Bone.  2014; 62: 79-89.
  • Jonason JH and O’Keefe RJ.  Isolation and culture of neonatal mouse calvarial osteoblasts.  Methods Mol Biol.  2014; 1130: 295-305.
  • Li TF, Yukata K, Yin G, Sheu T, Maruyama T, Jonason JH, Hsu W, Zhang X, Xiao G, Konttinen YT, Chen D, O'Keefe RJ.  BMP-2 induces ATF4 phosphorylation in chondrocytes through a COX-2/PGE2 dependent signaling pathway.  Osteoarthritis Carilage.  2014; 22(3): 481-9.
  • 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 -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.

Graduate Program Affiliation

Lab Alumni

Sarah Catheline

Sarah Catheline