Professor and Chair
office: Brody 7N-100
B.A., Pomona College
Ph.D., University of Southern California
Postdoctoral Fellow, Tufts University School of Medicine
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.
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.
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 Rheum. 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. Osteoarthr. 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.
Ariyoshi W., T. Okinaga, C.B. Knudson, W. Knudson, and T. Nishihara. 2014. High molecular weight hyaluronic acid regulates osteoclast formation by inhibiting receptor activator of NF-κB ligand through Rho kinase. Osteoarthr. Cartilage 22:111-120.
Luo N., W. Knudson, E.B. Askew, R.M. Veluci, and C.B. Knudson. 2014. CD44 and hyaluronan promote the bone morphogenetic protein 7 signaling response in murine chondrocytes. Arthritis Rheum. 66:1547-1558.
"Hyaluronan-Cell Interactions in Cartilage" (NIH R01 AR039507); Cheryl B. Knudson, Principal Investigator; National Institute of Arthritis and Musculoskeletal and Skin Diseases; 7/1/2009-6/30/2015.
Location: 7N-100, 7E-118, & 8E-16
|Michelle Cobb||Research Technicianfirstname.lastname@example.org|
|Crystal Hooper||Admin. Support Assistantemail@example.com|
|Ann Sadler||Admin. Support Assistantfirstname.lastname@example.org|
|Samantha Sellers||Graduate Studentemail@example.com|
|Joani Zary-Oswald||Research Technician, Core Labfirstname.lastname@example.org|
|Dean J. Aguiar, Ph.D.||Director of Product Development||BioMimetic Therapeutics, Franklin, TN|
|Roma A. Andhare, Ph.D.||Assistant Professor||Department of Chemistry, Oakton Community College, Des Plaines, 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|