. Osteoarthritis (OA) is the most common arthritic condition in the U.S.A., and is responsible in aggregate for vast economic costs, due both to direct medical care and to lost work days. OA is primarily a degenerative process of articular cartilage and our research focus is to identify strategies to stimulate cartilage matrix repair. In cartilage, cell-matrix interactions are the primary means for chondrocytes to sense changes in the extracellular environment, and signal a reparative response. Hyaluronan (HA) binding to the CD44 receptor is a key player in such interactions. Since HA-CD44 interactions are required for the retention of proteoglycan in the matrix, the relationship between these components is crucial to cartilage homeostasis. For chondrocytes, CD44 signaling is initiated by disruption of HA-CD44 interactions and thus declustering of CD44. Loss of HA- CD44 interactions exerts a negative effect on the canonical BMP/BMP-R/Smad1 signaling pathway that can be rescued by the addition of HA. Furthermore, changes in HA-CD44 interactions initiated other signaling cascades resulting in the stimulation of genes for matrix turnover (MMP-3, MMP-13, iNOS) and for matrix repair (collagen II, aggrecan, HAS2, BMP7). As such this exciting discovery defines a new chondrocyte-based model that closely mimics the early stage of OA namely, """"""""attempted repair"""""""" but repair that is coincident with enhanced matrix degradation.
The first aim will define the signaling events initiated by the loss of cell-matrix interactions in chondrocytes that give rise to stimulation of both matrix repair and matrix degradation. Both loss-of-function and augmentation-of-function approaches with murine, bovine and human chondrocytes will be taken to discern the role of CD44 in the responses. In the second aim, the chondrocyte dedifferentiation/re- differentiation model will be used. Dedifferentiated articular chondrocytes exhibit changes in phenotype, some of which mimic osteoarthritic chondrocytes, importantly a reduced capacity for repair. Dedifferentiated chondrocytes exhibit a naturally-occurring degradation (shedding) of the CD44 extracellular domain as well as a ?secretase-mediated generation of the CD44 intracellular domain (ICD) which could initiate CD44 declustering. Nevertheless, these cells are capable of re-differentiation to a more """"""""chondrocyte-like"""""""" phenotype. The mechanism for this reversion is related to changes in the matrix, the cytoskeleton and in intracellular signaling - all events that could be mediated by CD44 and will be examined in our studies. Accordantly, chondrocytes from OA patient also exhibit CD44 fragmentation and the potential for re-differentiation of human OA cells will also be examined.
In specific aim 3, our hypothesis that HA-CD44 interactions enhance cartilage repair will be examined in studies on the formation of ectopic cartilage in vivo in CD44 knockout and wildtype mice and the generation of neo-cartilage disks in vitro. Together these aims will contribute to our understanding of HA-CD44 interactions in the regulation of chondrocyte metabolism.

Public Health Relevance

During the early states of osteoarthritis the cells of cartilage make an attempt at repair but this response ultimately fails and the cartilage tissue progressively deteriorates. Our studies model this early phase of degeneration and repair. Our goal is to determine how to enhance genes that will favor repair and thus prevent or delay the onset/progression of osteoarthritis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Tyree, Bernadette
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East Carolina University
Anatomy/Cell Biology
Schools of Medicine
United States
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Knudson, Warren; Ishizuka, Shinya; Terabe, Kenya et al. (2018) The pericellular hyaluronan of articular chondrocytes. Matrix Biol :
Terabe, Kenya; Takahashi, Nobunori; Takemoto, Toki et al. (2016) Simvastatin inhibits CD44 fragmentation in chondrocytes. Arch Biochem Biophys 604:1-10
Huang, Yi; Askew, Emily B; Knudson, Cheryl B et al. (2016) CRISPR/Cas9 knockout of HAS2 in rat chondrosarcoma chondrocytes demonstrates the requirement of hyaluronan for aggrecan retention. Matrix Biol 56:74-94
Ishizuka, Shinya; Askew, Emily B; Ishizuka, Naoko et al. (2016) 4-Methylumbelliferone Diminishes Catabolically Activated Articular Chondrocytes and Cartilage Explants via a Mechanism Independent of Hyaluronan Inhibition. J Biol Chem 291:12087-104
Danielson, Ben T; Knudson, Cheryl B; Knudson, Warren (2015) Extracellular processing of the cartilage proteoglycan aggregate and its effect on CD44-mediated internalization of hyaluronan. J Biol Chem 290:9555-70
Hida, Daisuke; Danielson, Ben T; Knudson, Cheryl B et al. (2015) CD44 knock-down in bovine and human chondrocytes results in release of bound HYAL2. Matrix Biol 48:42-54
Luo, Na; Knudson, Warren; Askew, Emily B et al. (2014) CD44 and hyaluronan promote the bone morphogenetic protein 7 signaling response in murine chondrocytes. Arthritis Rheumatol 66:1547-58
Ono, Yohei; Ishizuka, Shinya; Knudson, Cheryl B et al. (2014) Chondroprotective Effect of Kartogenin on CD44-Mediated Functions in Articular Cartilage and Chondrocytes. Cartilage 5:172-80
Ono, Yohei; Sakai, Tadahiro; Hiraiwa, Hideki et al. (2013) Chondrogenic capacity and alterations in hyaluronan synthesis of cultured human osteoarthritic chondrocytes. Biochem Biophys Res Commun 435:733-9
Mellor, Liliana; Knudson, Cheryl B; Hida, Daisuke et al. (2013) Intracellular domain fragment of CD44 alters CD44 function in chondrocytes. J Biol Chem 288:25838-50

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