The degenerative process in osteoarthritis involves changes in the metabolism of the chondrocytes and results in loss of extracellular matrix, especially proteoglycans (PG), leading to tissue fatigue and eventually joint failure. Hyaluronan (HA) is a key player in organizing and retaining PG in the cartilage, but little is known about this macromolecule's turnover and catabolism. During the last four year funding period, the investigators have shown that: (1) internalization of HA is mediated by CD-44; (2) internalized HA is degraded in lysosomes; (3) IL-1 and similar agents increase CD-44 expression, HA internalization, and HA and PG loss from the cartilage matrix; and (4) CD-44 expression is increased in osteoarthritic cartilage. The questions to be addressed in the next funding period are whether cellular uptake is the major catabolic pathway for HA and whether CD-44 is the only, or a major mediator of HA internalization. The following Specific Aims are proposed: (1) to inhibit lysosomal enzymes related to HA catabolism; (2) to express mutant CD-44 isoforms that are internalization defective and thus inhibit HA catabolism; and (3) to determine the effects on HA catabolism from overexpression of lysosomal hyaluronidase (HYAL-2).

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR043384-05
Application #
6193969
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Tyree, Bernadette
Project Start
1996-09-30
Project End
2005-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
5
Fiscal Year
2000
Total Cost
$281,287
Indirect Cost
Name
Rush University Medical Center
Department
Type
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
Knudson, Warren; Ishizuka, Shinya; Terabe, Kenya et al. (2018) The pericellular hyaluronan of articular chondrocytes. Matrix Biol :
Danielson, Ben T; Knudson, Cheryl B; Knudson, Warren (2015) Extracellular processing of the cartilage proteoglycan aggregate and its effect on CD44-mediated internalization of hyaluronan. J Biol Chem 290:9555-70
Hida, Daisuke; Danielson, Ben T; Knudson, Cheryl B et al. (2015) CD44 knock-down in bovine and human chondrocytes results in release of bound HYAL2. Matrix Biol 48:42-54
Luo, Na; Knudson, Warren; Askew, Emily B et al. (2014) CD44 and hyaluronan promote the bone morphogenetic protein 7 signaling response in murine chondrocytes. Arthritis Rheumatol 66:1547-58
Ariyoshi, W; Okinaga, T; Knudson, C B et al. (2014) High molecular weight hyaluronic acid regulates osteoclast formation by inhibiting receptor activator of NF-*B ligand through Rho kinase. Osteoarthritis Cartilage 22:111-20
Ono, Yohei; Sakai, Tadahiro; Hiraiwa, Hideki et al. (2013) Chondrogenic capacity and alterations in hyaluronan synthesis of cultured human osteoarthritic chondrocytes. Biochem Biophys Res Commun 435:733-9
Mellor, Liliana; Knudson, Cheryl B; Hida, Daisuke et al. (2013) Intracellular domain fragment of CD44 alters CD44 function in chondrocytes. J Biol Chem 288:25838-50
Ariyoshi, Wataru; Takahashi, Nobunori; Hida, Daisuke et al. (2012) Mechanisms involved in enhancement of the expression and function of aggrecanases by hyaluronan oligosaccharides. Arthritis Rheum 64:187-97
Patchigolla, R Krishna R; Knudson, Warren; Schmid, Thomas M (2012) Matrix metalloproteinase-9 in a unique proteoglycan form in avian embryonic growth plate cartilage. Arch Biochem Biophys 520:42-50
Takahashi, Nobunori; Knudson, Cheryl B; Thankamony, Sai et al. (2010) Induction of CD44 cleavage in articular chondrocytes. Arthritis Rheum 62:1338-48

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