Warren Knudson, Ph.D.

Warren Knudson, Ph.D.

Professor

B.S., Elmhurst College
Ph.D., University of Illinois at Urbana-Champaign
Postdoctoral Fellow, Tufts University School of Medicine

office: Brody 7N-86
telephone: 252-744-3483
e-mail: knudsonw@ecu.edu

Research
My laboratory studies the role and regulation of an extracellular matrix macromolecule named hyaluronan. Hyaluronan has been of interest to investigators because its expression is closely timed with the migration of cells during embryonic development as well as invasive migration of malignant cells. Hyaluronan also is a major lubricant in synovial joints and serves as an organizing filament of the extracellular matrix of articular cartilage. Changes in hyaluronan in the latter tissue may underlie the destruction of cartilage that occurs in degenerative osteoarthritis. To understand the regulation of hyaluronan in all of these systems, we have focused on the enzymes that synthesize hyaluronan (hyaluronan synthases), cellular hyaluronidases and the principal hyaluronan receptor, CD44. For example, in recent years we have cloned two of three critical lysosomal hyaluronidases to examine their function and distribution, inhibited their activity by siRNA and antisense oligonucleotides and characterized the promoter of region of the HYAL-2 hyaluronidase.

However, the hyaluronan receptor, CD44, is the major focus of my laboratory. CD44 retains hyaluronan to the plasma membrane of many cell types including carcinoma cells, embryonic mesenchyme, and adult chondrocytes. We have shown that changes in receptor occupancy affect signaling events via p38 MAPK pathways and NF-κB resulting in increases in the matrix metalloproteinases, MMP-3 and MMP-13. CD44 also mediates the endocytosis of hyaluronan and as such, serves as the major route of catabolic turnover of hyaluronan. In many cells, regulation of hyaluronan turnover is more important to its expression than biosynthesis. To address this issue we have generated point mutations within full length CD44 and artificially-truncated isoforms of CD44. With this approach we have determined the critical motifs within the CD44 intracellular tail domain that are necessary for CD44 to participate in endocytosis as well as the cellular mechanisms that regulate this event.

Selected Publications
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.

Chow, G., C.B. Knudson, G. Homandberg, and W. Knudson. 1995. Increased expression of CD44 in bovine articular chondrocytes by catabolic cellular mediators. J. Biol. Chem. 270:27734-27741.

Nishida Y., C.B. Knudson, J.J. Nietfeld, A. Margulis, and W. Knudson. 1999. Antisense inhibition of hyaluronan synthase-2 in human articular chondrocytes inhibits proteoglycan retention and matrix assembly. J. Biol. Chem. 274: 21893-21899.

Jiang H., C.B. Knudson, and W. Knudson. 2001. Antisense inhibition of CD44 tailless splice variant in humanarticular 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.

Embry, J.J. and W. Knudson. 2003. The G1 domain of aggrecan is co-internalized with hyaluronan via a CD44-mediated mechanism in bovine articular chondrocytes. Arthritis & Rheumatism 48: 3431-3441.

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.

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.

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.

Chow, G. and W. Knudson. 2005. Characterization of promoter elements of the human HYAL-2 gene. J. Biol. Chem. 280: 26904-26912.

Embry, J.J., A.J. Fosang, and W. Knudson. 2006. Extracellular hyaluronan binding is necessary for the intracellular accumulation of ITEGE epitope in bovine articular chondrocytes. Arthritis & Rheumatism 54: 443-454.

Chow, G., C.B. Knudson, and W. Knudson. 2006. Expression and cellular localization of human hyaluronidase-2 in articular chondrocytes and cultured cell lines. Osteoarthritis and Cartilage in press (available on-line).

Ohno, S., T. Schmid, Y. Tanne, T. Kamiya, K. Honda, M. Ohno-Nakahara, N. Swentko, T.A. Desai, K. Tanne, C.B. Knudson, and W. Knudson. 2006. Expression of superficial zone protein in mandibular condyle cartilage. Osteoarthritis and Cartilage in press (available on-line).

Ohno S., H.-J. Im, C.B. Knudson, and W. Knudson. 2006. Hyaluronan oligosaccharides induce MMP-13 via transcriptional activation of NFkB and p38 MAP kinases in articular chondrocytes. J. Biol. Chem in press (available on-line).

Click PubMed Publications for further listings.

Current Funding
"CD44 Mediated Catabolism of Hyaluronan by Chondrocytes"; Warren Knudson, Principal Investigator; National Institute of Arthritis and Musculoskeletal and Skin Diseases; 9/1/05-8/31/10.

"Hyaluronan-Cell Interactions in Cartilage"; Warren Knudson, Co-Investigator; National Institute of Arthritis and Musculoskeletal and Skin Diseases; 4/1/02-3/31/07.

Staff and Students
Location 7N-86

Name	Title	Phone	E-Mail
Jarrett Devine	Research Technician	744-3467	devinej@ecu.edu