ADVERSE EFFECT OF HA-BINDING PROTEINS IN OSTEOARTHRITIS

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DESCRIPTION (Taken from the application): The high-density cartilage proteoglycan (aggrecan) binds to hyaluronic acid (hyaluronan; HA) and this interaction is stabilized by a third component: "link protein". The major physiological function of aggrecan is to bind water, via its glycosaminoglycan (GAG) side chains, providing resilience for the weight-bearing articular cartilage. Due to the turnover of aggrecan, the core protein of the aggrecan is cleaved by various metalloproteinases and, while the GAG-attachment regions are preferentially lost, the N-terminal end of the molecule bound to HA is retained. In contrast to normal aging processes, extracellular matrix molecules are more extensively degraded in osteoarthritis, and both the HA-binding (Gl) domain of aggrecan and link protein progressively accumulate in osteoarthritic cartilage. Resident chondrocytes attempt to repair cartilage by increased matrix synthesis, but these newly synthesized molecules are also lost either due to their increased degradation or reduced retention. We hypothesize that the accumulation of HA-binding proteins (G1 domain of aggrecan and link protein) in cartilage can competitively inhibit the retention of the newly synthesized HA-binding molecules, and this process results in the loss of aggrecan (the water-binding capacity of cartilage), thus the loss of function of articular cartilage. We propose to investigate the in vivo consequence of manipulating the aggrecan/HA and link protein/HA-binding interactions, through transgenic approaches. We will attempt to accelerate and simulate early cartilage damage by overexpressing G1 domain and link protein in order to gain insight into the (patho)physiological role of HA-binding proteins in osteoarthritic cartilages.