B.A., Pomona College
Ph.D., University of Southern California
Postdoctoral Fellow, Tufts University School of Medicine

office: Brody 7N-100
telephone: 252-744-2852
e-mail: knudsonc@ecu.edu

| Research | Reviews | Selected Publications | Current Funding | Staff and Students |

Research
The overall research goals of our laboratory are to determine role of cell-matrix interactions during embryonic development, tissue homeostasis and the modulation of the cellular response to growth factors. Our results support the paradigm that information from the extracellular matrix is communicated through cellular receptors that provide signals that ultimately affect cell metabolism. The current focus of research is one macromolecule of the extracellular matrix, hyaluronan, and its receptor CD44 and the implications of their interactions on tissue remodeling or degeneration.

One prominent feature of osteoarthritic cartilage is an inherent failure to retain proteoglycan-rich extracellular matrix. The hypothesis of our laboratory is that part of the overall failure in this degenerative disease is due to a change in the number or function of matrix receptors. Our work demonstrated that chondrocytes tether proteoglycan aggregates through the binding of hyaluronan to the receptor CD44 and that matrix assembly and retention is regulated by the expression of functional CD44. CD44 also mediates the endocytosis and catabolism of the extracellular matrix and signals compositional or mechanical changes within the extracellular matrix.

The biological consequence of disruption of the interaction of HA with functional CD44 receptors is the induction of matrix turnover as well as matrix biosynthesis -- replicating a chondrocyte response that partners attempted repair with enhanced catabolism, hallmarks of osteoarthritis (OA) and other degenerative diseases. Current aims explore the contribution of HA-CD44 interactions to the regulation of chondrocyte metabolism.

The cytoplasmic domain of CD44 exhibits no inherent receptor kinase or phosphatase activity but CD44 can serve as a functional link to other signaling pathways. Therefore formation and/or uncoupling of HA-CD44 interactions modulate cell signaling. We have validated the interaction of CD44 with Smad1, a receptor-regulated transcriptional modulator in the canonical BMP signaling pathway. Current investigations to determine the negative effect of the loss of HA-CD44 interactions on BMP7-mediated signaling events combine loss and gain-of-function approaches. This new paradigm of CD44-Smad1 interactions may provide a mechanism to explain how changes in the extracellular matrix influence cell metabolism.

The cleavage of CD44 first generates an extracellular fragment which is shed plus a C-terminal fragment that subsequently becomes a substrate by which the CD44 intracellular domain (ICD) is generated. The ectodomain of CD44 and the CD44-ICD are generated by naturally-occurring mechanisms in dedifferentiating chondrocytes as well as chondrocytes from osteoarthritic cartilage. Augmentation of CD44 or CD44-partners may promote cartilage tissue biogenesis.

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Reviews
Knudson, C.B. and W. Knudson. 1993. Hyaluronan binding proteins in development, tissue homeostasis and disease. FASEB J. 7: 1233-1241 

Knudson, C.B. and W. Knudson. 2001. Cartilage proteoglycans. Seminars in Cell & Developmental Biology 12: 69-78. 

Knudson, C.B. 2003. Hyaluronan and CD44: Strategic players for cell-matrix interactions during chondrogenesis and matrix assembly. Birth Defects Research Part C: Embryo Today 69: 174-196. 

Knudson, W. and C.B. Knudson. 2005. The hyaluronan receptor, CD44 – An update. Glycoforum – Hyaluronan Today.

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Selected Publications
Knudson, C.B. 1993. Hyaluronan receptor-directed assembly of chondrocyte pericellular matrix. J. Cell Biol. 120: 825-834. 

Knudson W., E. Bartnik, and C.B. Knudson. 1993. Assembly of pericellular matrix by COS-7 cells transfected with CD44 homing receptor genes. Proc. Natl. Acad. Sci. USA 90: 4003-4007. 

Aguiar, D.J., W. Knudson, and C.B. Knudson. 1999. Internalization of CD44 by bovine articular chondrocytes. Exp. Cell Res. 252: 292-302. 

Nishida Y., C.B. Knudson, W. Eger, K.E. Kuettner, and W. Knudson. 2000. Hyaluronan oligosaccharides perturb cartilage matrix homeostasis and induce cartilage chondrolysis. Arthritis & Rheumatism 43: 1165-1174. 

Nishida Y., C.B. Knudson, W. Eger, K.E. Kuettner, and W. Knudson. 2000. Osteogenic Protein-1 stimulates cell-associated matrix assembly by normal human articular chondrocytes: Upregulation of hyaluronan synthase, CD44, and aggrecan. Arthritis & Rheumatism 43: 206-214. 

Jiang H., C.B. Knudson, and W. Knudson. 2001. Antisense inhibition of CD44 tailless splice variant in human articular chondrocytes promotes hyaluronan internalization. Arthritis & Rheumatism 44: 2599-2610. 

Jiang H., R.S. Peterson, W. Wang, E. Bartnik, C.B. Knudson, and W, Knudson. 2002. A requirement for the CD44 cytoplasmic domain for hyaluronan binding, pericellular matrix assembly and receptor mediated endocytosis in COS-7 cells. J. Biol. Chem. 277: 10531-10538. 

Rousche, K.T. and C.B. Knudson. 2002. Temporal expression of CD44 during embryonic chick limb development and modulation of its expression with retinoic acid. Matrix Biol. 21: 53-62. 

Nofal, G.A. and C.B. Knudson. 2002. Latrunculin and cytochalasin decrease chondrocyte matrix retention. J. Histochem. Cytochem. 50: 1313-1324. 

Ohno-Nakahara, M., K. Honda, K. Tanimoto, N. Tanaka, T. Doi, A. Suzuki, K. Yoneno, Y. Nakatani, M. Ueki, S. Ohno, W. Knudson, C.B. Knudson, and K. Tanne. 2004. Induction of CD44 and MMP expression by hyaluronidase treatment of articular chondrocytes. J. Biochem. (Tokyo) 135: 567-575. 

Nishida, N., C.B. Knudson, and W. Knudson. 2004. Osteogenic Protein-1 inhibits matrix depletion in a hyaluronan hexasaccharide-induced model of osteoarthritis. Osteoarthritis and Cartilage 12: 374-382. 

Peterson, R.S., R.A. Andhare, K.T. Rousche, W. Knudson, W. Wang, J.B. Grossfield, R.O. Thomas, R.E. Hollingsworth, and C.B. Knudson. 2004. CD44 modulates Smad1 activation in the BMP-7 signaling pathway. J. Cell Biol. 166: 1081-1091. 

Nishida, Y., W. Knudson, C.B. Knudson, and N. Ishiguro. 2005. Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity. Exp. Cell Res. 307: 194-203. 

Ohno, S., H.-J. Im, C. Knudson, and W. Knudson. 2005. Hyaluronan oligosaccharide-induced activation of transcription factors in bovine articular chondrocytes. Arthritis & Rheumatism 52: 800-809. 

Iacob S. and C.B. Knudson. 2006. Hyaluronan fragments activate nitric oxide synthase and the release of nitric oxide in articular chondrocytes. Int. J. Biochem. Cell Biol. 38: 123-133. 

Ohno S., H.-J. Im, C.B. Knudson, and W. Knudson. 2006. Hyaluronan oligosaccharides induce matrix metalloproteinase 13 via transcriptional activation of NFkappaB and p38 MAP kinase in articular chondrocytes. J. Biol. Chem. 281: 17952-17960. 

Andhare, R.A., N. Takahashi, W. Knudson, and C.B. Knudson. 2009. Hyaluronan promotes the chondrocyte response to BMP-7. Osteoarthritis and Cartilage 17: 906-916. 

Takahashi N., C.B. Knudson, S. Thankamony, W. Ariyoshi, L. Mellor, H.-J. Im, and W. Knudson. 2010. Induction of CD44 cleavage in articular chondrocytes. Arthritis & Rheumatism 62: 1338-1348.

Ariyoshi, W., C.B. Knudson, N. Luo, A.J. Fosang, and W. Knudson. 2010. Internalization of aggrecan G1 domain neoepitope ITEGE in chondrocytes requires CD44. J .Biol. Chem. 285:36216-36224.

Click PubMed Publications for further listings.

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Current Funding
"Hyaluronan-Cell Interactions in Cartilage" (NIH R01 AR039507); Cheryl B. Knudson, Principal Investigator; National Institute of Arthritis and Musculoskeletal and Skin Diseases; 7/1/2009-6/30/2014.

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Staff and Students
Location 7N-100, 7E-118, & 8E-16

Former Students and Post-Doctoral Fellows:

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