Cell-matrix interactions, which occur via the specific binding of matrix macromolecules to cell surface receptors, control many aspects of assembly, retention and matrix-cell signaling within the extracellular matrix. One consistent observation, in either experimental animal models of osteoarthritis or in human osteoarthritis, is the lack of retention of proteoglycans by articular cartilage. It is also clear that, in the early stages of the disease, chondrocytes mount a substantial biosynthetic response to counter the deficit. Nonetheless, often this response is not sufficient and does not lead to successful repair. The proteoglycans are not retained by the cartilage, proteoglycan loss continues, as does the disease progression. One likely defect is a reduction in the capacity of chondrocytes to actively retain or anchor their proteoglycan-rich matrix. We have identified the cell surface glycoprotein CD44 as the primary receptor for HA on chondrocytes. Our data have demonstrated that the proteoglycan-rich portion of the cartilage extracellular matrix is anchored to the chondrocyte plasma membrane via CD44. This linkage allows the chondrocytes a means of direct control over matrix assembly and retention. Our hypothesis is that the regulated expression of functional CD44 regulates matrix assembly and retention by chondrocytes. We have determined that chondrocytes minimally express the standard CD44 isoform, CD44v10, and the short cytoplasmic tail CD44-exon18 isoform. We have found that matrix-intact chondrocytes have increased ser/thr phosphorylation of CD44 and enhanced CD44 association with the cytoskeleton compared with matrix-depleted chondrocytes.
Specific aim number 1 will test the hypothesis that chondrocytes regulate matrix assembly and retention via expression of particular alternatively spliced CD44 isoforms and via regulated association of CD44 isoforms with the cytoskeleton.
Specific aim number 2 will address the hypothesis that CD44 function in matrix assembly and retention becomes disregulated or otherwise altered in osteoarthritis, especially during early phases of attempted but failing repair.
Aim 2 involves experiments with human articular cartilage and using a rabbit model of articular cartilage degeneration.
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