ADVERSE EFFECT OF HA-BINDING PROTEINS IN OSTEOARTHRITIS

描述（取自应用程序）： 高密度软骨蛋白聚糖（聚集蛋白聚糖）与透明质酸结合 （透明质酸; HA），这种相互作用由第三种成分稳定： 蛋白质”。聚集蛋白聚糖的主要生理功能是结合水， 它的糖胺聚糖（GAG）侧链，提供弹性， 承重关节软骨 由于聚集蛋白聚糖的周转，聚集蛋白聚糖的核心蛋白被蛋白酶切割。 各种金属蛋白酶，而GAG附着区是 当结合到HA的分子的N-末端优先丢失时， 保留。与正常的衰老过程相反，细胞外基质分子 在骨关节炎中更广泛地降解，并且HA结合（GI） 聚集蛋白聚糖和连接蛋白结构域在骨关节炎中进行性积累 软骨常驻软骨细胞试图通过增加 基质合成，但这些新合成的分子也会丢失， 这是由于它们的降解增加或保留减少。我们假设 HA结合蛋白（聚集蛋白聚糖G1结构域和接头 蛋白质）可以竞争性地抑制新的 合成HA结合分子，并且该过程导致HA结合分子的损失。 聚集蛋白聚糖（软骨的水结合能力），从而丧失功能 关节软骨 我们建议调查在体内的后果操纵的 聚集蛋白聚糖/HA和连接蛋白/HA结合相互作用，通过转基因 接近。我们将尝试加速和模拟早期软骨损伤 通过过表达G1结构域和连接蛋白， HA结合蛋白在骨关节炎软骨中的（病理）生理作用。

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.