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 glycosaminoglycan hyaluronan is a ubiquitous extracellular matrix macromolecule. The identification of hyaluronan in many locations where stem cells are present implicates an important role. Modulation of cell-matrix interactions functions as a rheostat to alter cellular metabolism and signaling involved in tissue homeostasis, development and disease processes. As connective tissues form by cellular condensations, there is a loss of cell-associated hyaluronan to facilitate cell-to-cell adhesion. In cartilage, hyaluronan serves to retain aggrecan in the extracellular matrix; but also provides the tether of these matrix components to the chondrocyte cell surface through its receptor CD44.
Chondrocytes from human osteoarthritic (OA) cartilage often are hyaluronan deficient. Hyaluronan deficiencies can be generated experimentally and often result in elevated production of MMPs as well as the release of NO and in cartilage explants, the loss of Safranin O staining. Reducing hyaluronan-cell interactions induces these catabolic cascades by activation of signaling pathways that involve NF-κB and p38 MAPK. On the anabolic arm, reduction in hyaluronan-cell interactions diminishes the cellular response to BMP7 but not to TGF-β1.
Interestingly, CD44 may again be part of this hyaluronan story based on its susceptibility to proteolytic fragmentation. Substantial levels of CD44 fragments are present in direct extracts of OA cartilage and, chondrocytes obtained from OA patients exhibit substantially enhanced CD44 proteolysis that can be blocked by inhibitors of membrane-bound proteases. The released CD44-ECD fragments represent one group of DAMPs (damage associated molecular patterns) that participate in innate immune activation of chondrocytes. The production of hyaluronan by chondrocytes acts to diminish DAMP-mediated responses. Thus our ongoing research links the “wear and tear” concept of OA with the emerging paradigm of auto-inflammation or innate immunity in OA.
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.
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.
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.
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.
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.
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.
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.
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Location: 7N-100, 7E-118, & 8E-16