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).
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