office: Brody 7N-86A
B.S., Elmhurst College
Ph.D., University of Illinois at Urbana-Champaign
Postdoctoral Fellow, Tufts University School of Medicine
My laboratory studies the role of cell-extracellular matrix interactions and how they influence cell behavior. One extracellular matrix macromolecule in particular, named hyaluronan, has been of interest because its expression is closely timed with cell migration during embryonic development as well as the 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 cartilage 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 that degrade hyaluronan and the principal hyaluronan receptor, CD44. We have characterized cell signaling events mediated via CD44—events that trigger changes in p38 MAPK, Akt and NF-κB dependent pathways. Activation of these pathways results in increased expression of various matrix metalloproteinases and ADAMs. 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 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. Cells and tissues from CD44-/- mice are also examined to confirm the role and participation of CD44 in various cell-extracellular matrix interactions.
Current research also includes investigations into: 1) CD44 proteolytic fragmentation associated with enhanced cellular degradation, including the effects of release of CD44–intracellular domains; 2) the development of genetically-altered bioengineered cartilage tissues; 3) gene transfer into cells and intact tissues such as cartilage using adeno and adeno-associated virus constructs and; 3) co-internalization of aggrecan fragments via hyaluronan-CD44 mediated pathways. Our laboratory also investigates the participation of CD44 in other cellular processes including directing the cell fate of mesenchymal stem cells, cancer stem cells and other cells undergoing epithelial-mesenchymal transitions.
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., 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.
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.
Chow, G. and
W. Knudson. 2005. Characterization of promoter elements of the human HYAL-2 gene. J. Biol. Chem. 280: 26904-26912.
Ohno, S., H-E. Im, C.B. Knudson, and
W. Knudson. 2006. Hyaluronan oligosaccharide enhances the MMP-13 induction via transcriptional activation of NFkB. J. Biol. Chem. 281:17952-17960, 2006.
Thankamony, S. and
W. Knudson. 2006. Acylation of CD44 and its association with lipid rafts are required for receptor and hyaluronan endocytosis. J. Biol. Chem. 281:34601-34609.
Hosono, K., Y. Nishida,
W. Knudson, C.B. Knudson, T. Naruse, Y. Suzuki, and N. Ishiguro. 2007. Hyaluronan oligosaccharides inhibit tumorigenicity of osteosarcoma cell line, MG-63 and LM-8 in vitro and in vivo via perturbation of hyaluronan rich pericellular matrix of the cells. Am. J. Path. 171:274-286.
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 Rheum. 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.
Ariyoshi, W., N. Takahashi, D. Hida, C.B. Knudson, and
W. Knudson. 2012. Mechanisms involved in enhancement of the expression and function of aggrecanases by hyaluronan oligosaccharides. Arthritis Rheum. 64:187-197.
Urakawa, H., Y. Nishida,
W. Knudson, C.B. Knudson, E. Arai, E. Kozawa, N. Futamura, J. Wasa, and N. Ishiguro. 2012. Therapeutic potential of hyaluronan oligosaccharides for bone metastasis of breast cancer. J. Orthop. Res. 30: 662-672.
W. Knudson, and T.M. Schmid. 2012. Matrix metalloproteinase-9 in a unique proteoglycan form in avian embryonic growth plate cartilage. Arch. Biochem. Biophys. 520: 42-50.
Mellor, L.F., 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 osteoclastogenesis by inhibiting receptor activator of NF-κB ligand through Rho kinase. Osteoarthr. Cartilage 22: 111-120.
W. Knudson, E.B. Askew, R. Veluci, and C.B. Knudson. 2014. CD44 and hyaluronan promote the bone morphogenetic protein 7 signaling response in chondrocytes. Arthritis Rheum. 66: 1547-1558.
Ono Y., S. Ishizuka, C.B. Knudson, and
W. Knudson. 2014. Chondroprotective effect of kartogenin on CD44-mediated functions in articular cartilage and chondrocytes. Cartilage 5: 172-180.
Danielson, B.T., C.B. Knudson, and
W. Knudson. 2015. Extracellular processing of the cartilage proteoglycan aggregate and its effect on CD44-mediated internalization of hyaluronan. J. Biol. Chem. 290: 9555-9570.
Yuang, Y., E.B. Askew, C.B. Knudson, and W. Knudson. 2016. CRISPR/Cas9 knockout of HAS2 in rat chondrosarcoma chondrocytes demonstrates the requirement of hyaluronan for aggrecan retention. Matrix Biol. 56: 74-94.
Ishizuka, S., E.B. Askew, N. Ishizuka, C.B. Knudson, and W. Knudson. 2016. 4-methyl-umbelliferone diminishes catabolically-activated articular chondrocytes and cartilage explants via a mechanism independent of hyaluronan inhibition. J. Biol. Chem. 291: 12087-12104.
Terabe, K., N. Takahashi, T. Takemoto, W. Knudson, N. Ishiguro, and T. Kojima. 2016. Simvastatin inhibits CD44 fragmentation in chondrocytes. Arch Biochem Biophys. 604: 1-10.
View PubMed Publications for further listings
"Altering the Intracellular Flux in UDP-hexose Pools Provides Chondroprotection" (NIH R21 AR072682); Warren Knudson, Principal Investigator, National Institute for Arthritis and Musculoskeletal Diseases 9/21/2017-8/31/2019.
"Cartilage Hyaluronan and CD44 in the Age of DAMPs." Warren Knudson, Principal Investigator; Mizutani Foundation for Glycoscience; 4/1/2017-3/31/2019.