Cheryl B. Knudson, Ph.D.

Professor and Chair

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 | Selected Publications | Current Funding | Staff and Students |

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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. Ongoing studies on the mechanism of regulation of functional CD44 expression include changes in the phosphorylation and/or association of cytoplasmic domain of CD44 with the cytoskeleton and analysis of CD44 promotor elements.

Disruption of CD44-hyaluronan interactions (by antisense approaches, hyaluronan oligosaccharides, cytoskeletal disruption) results in cartilage damage coupled with enhanced biosynthesis. Another exciting observation is that human articular chondrocytes also express a naturally-occurring dominant negative isoform of CD44, termed CD44exon19. This alternatively-spliced, truncated receptor selectively interferes with the interaction of hyaluronan and wildtype CD44. As such, the expression of this isoform disrupts the retention of the hyaluronan-rich extracellular matrix to the chondrocytes, activating the alternative signaling cascades. Although a minor transcript in many human chondrocytes, we have found chondrocytes from some donors express relatively high levels of CD44exon19.

To explore pathways that utilize CD44 to transduce changes in the matrix to alter chondrocyte metabolism, a yeast two hybrid (Y2H) screen was performed. This led to the interesting discovery that Smad1, a signaling partner associated with bone morphogenetic protein (BMP) receptors, interacts with the cytoplasmic tail domain of CD44. No interaction was observed using the truncated CD44 cytoplasmic domain. The overall aim of one project is to investigate the dual role of CD44 as a matrix receptor and a binding partner of Smad1 and how this role may represent a mechanism for cells to "sense" and "respond" to changes in their extracellular environment. Thus alteration of the CD44-bound extracellular matrix or, modulation of functional CD44 may alter the cellular response to BMPs. Given the role that hyaluronan, CD44 and BMPs play in chondrogenesis, the function of hyaluronan:CD44:Smad1 interactions in chondrogenesis is also under investigation as a natural extension of these studies. Thus, this new paradigm of CD44-Smad1 interactions may provide a mechanism to explain how changes in the extracellular matrix influence cell metabolism.

Since over-expression of the CD44 dominant negative receptor disrupts cell-hyaluronan interactions, another project is to determine the signaling pathways activated by the loss of hyaluronan-chondrocyte interactions and characterize the mechanisms for the dominant negative effects of CD44exon19 on CD44wt. Since hyaluronan-CD44 interactions regulate both anabolic and catabolic responses in chondrocytes, a disruption of this balance may be responsible for a shift toward cartilage degeneration. Also, it is likely that hyaluronan-CD44 interactions (or lack thereof) exert potent modulating influences on other signaling systems, i.e., mediated by growth factors or cytokines. Therefore, a long-term objective of this study is to provide a better understanding of how hyaluronan-CD44 coordinates with other signaling pathways to regulate metabolism.

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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.

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

Nishida, Y., W. Knudson, C.B. Knudson, and N. Ishiguro. 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.

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

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.

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.

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.

Knudson, W. and C.B. Knudson. 2005. The hyaluronan receptor, CD44 – An update. Glycoforum – Hyaluronan Today website (available on-line).

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.

Click PubMed Publications for further listings.

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Current Funding
"Hyaluronan-Cell Interactions in Cartilage"; Cheryl B. Knudson, Principal Investigator; National Institute of Arthritis and Musculoskeletal and Skin Diseases; 4/1/02-3/31/07.

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

Former Students and Post-Doctoral Fellows:

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