ADVERSE EFFECT OF HA-BINDING PROTEINS IN OSTEOARTHRITIS

描述(取自申请表)： 高密度软骨蛋白多糖(Aggrecan)与透明质酸结合 (透明质酸；HA)，这种相互作用由第三个成分稳定：“link Aggrecan的主要生理功能是结合水，通过 其糖胺多聚糖(GAG)侧链，为 承重关节软骨。 由于aggrecan的周转，aggrecan的核心蛋白被 各种金属蛋白酶，而插嘴附着区是 优先丢失，与HA结合的分子的N端是 保留。与正常的衰老过程不同，细胞外基质分子 在骨关节炎中被更广泛地降解，并且HA结合(Gl) 聚集素和连接蛋白结构域在骨关节病中的进行性积聚 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丢失了 由于它们的降解增加或保留率降低。我们假设 透明质酸结合蛋白(聚集素和LINK的G1结构域)的积累 蛋白)可以竞争性地抑制新生的 人工合成的HA结合分子，这一过程导致 聚集素(软骨的保水能力)，从而丧失功能 关节软骨。 我们建议研究在体内操纵的后果 通过转基因，aggrecan/HA和link蛋白/HA结合的相互作用 接近了。我们将尝试加速和模拟早期软骨损伤 通过过度表达G1结构域和连接蛋白来深入了解 骨关节炎软骨中HA结合蛋白的(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.