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The Brody School of Medicine
Department of Anatomy and Cell Biology






C
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 | 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 ongoing 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.

Hyaluronan is synthesized by hyaluronan synthases (HAS1-3), a family of plasma membrane enzymes, and is secreted into the extracellular matrix direct through the plasma membrane.  The functions of hyaluronan in the pericellular matrix include matrix assembly, regulation of conformational changes in the plasma membrane and cortical cytosolic events. 

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 cytoplasmic domain of CD44 exhibits no inherent receptor kinase or phosphatase activity but CD44 can serve as a functional link to other signaling pathways. The formation and/or uncoupling of hyaluronan-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. This new paradigm of CD44-Smad1 interactions may provide a mechanism to explain how changes in the extracellular matrix influence cell metabolism.

The biological consequence of disruption of the interaction of hyaluronan 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 hyaluronan-CD44 interactions to the regulation of chondrocyte metabolism.  Augmentation of CD44 or CD44-partners may promote cartilage tissue biogenesis and repair.

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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. 

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. 

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

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. 

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.

Mellor, L., C.B. Knudson, D. Hida, E.B. Askew, and W. Knudson. 2013. Intracellular domain fragment of CD44 alters CD44 function in chondrocytes.J. Biol. Chem. 288: 25838-25850.

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

Name Title Phone E-mail
Michelle Cobb Research Technician 744-3474 cobbkar@ecu.edu
Crystal Hooper Admin. Support Assistant 744-2851 hooperc@ecu.edu
John Powers Curator 744-2843 powersj@ecu.edu
Ann Sadler Admin. Support Assistant 744-2849 sadlera@ecu.edu
Samantha Sellers Graduate Student 744-3474 sellerssa12@students.ecu.edu
Joani Zary-Oswald Research Technician, Core Lab 744-2855 zaryj@ecu.edu


Former Students and Post-Doctoral Fellows:

Name Title Location
Dean J. Aguiar, Ph.D. Director of Product Development
BioMimetic Therapeutics, Franklin, TN
Roma A. Andhare, Ph.D. Instructor College of Dentistry, University of Illinois at Chicago, Chicago, IL
Ankit Desai, M.D. Assistant Professor Section of Cardiology, College of Medicine, University of Illinois at Chicago, Chicago, IL
Stanca Iacob, Ph.D., M.D.
Research Associate
Comprehensive Transplant Center, Department of Surgery, Northwestern University, Chicago, IL
Na Luo, Ph.D. Assistant Professor School of Medicine, Nankai University, Tianjin, P.R. China
Michael P. Maleski, Ph.D.
Deceased
Ghada A. Nofal, Ph.D. Pharmacist Chicago, IL
Maiko Ohno-Nakahara, Ph.D., D.D.S. Dentist Kobe, Japan
Pedram Pouryazdanparast, M.D. Anatomic Pathologist Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL
Eka A. Rapava, Ph.D. Chair Department of Biochemistry, Tbilisi State Medical University, Tbilisi, Georgia
Kathleen T. Rousche, Ph.D. Program Director
Office of Translational Alliances and Coordination, Division of Extramural Research Activities, National Heart, Lung and Blood Institute, Bethesda, MD

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