Matrix proteins promote matrix vesicle mineralization

描述（由申请人提供）：致病性钙晶体，包括焦磷酸钙（CPPD）和碱性磷酸钙（BCP）晶体，是骨关节炎关节的常见成分。这些晶体可以识别出一部分患有异常严重、快速进展性关节炎的患者。然而，晶体如何在正常的未矿化关节软骨基质中形成仍然未知。基质囊泡是膜结合的软骨细胞衍生的细胞外细胞器，参与钙晶体的形成。初步研究结果强烈表明，周围的软骨细胞外基质明显影响基质囊泡的矿化能力。生长板软骨中基质囊泡及其周围细胞外环境之间的重要相互作用有足够的优先权。虽然在骨关节炎和钙晶体沉积中关节软骨基质发生显著变化，但对关节软骨中细胞外基质和基质囊泡的相互作用知之甚少。我们假设基质囊泡和细胞外基质成分之间的相互作用强烈影响关节软骨基质囊泡产生病理性钙结晶的能力。 在这个提议中，我们将在基于凝胶的钙化模型中使用猪关节软骨基质囊泡来研究I）II型胶原对关节软骨基质囊泡矿化的影响，II）大蛋白聚糖和小蛋白聚糖对关节软骨基质囊泡矿化的影响，以及IN）钙结合蛋白的影响。（骨桥蛋白、骨桥蛋白和基质Gla蛋白）对关节软骨基质囊泡矿化的影响。 这项工作的最终目标是了解关节软骨中钙晶体形成的发病机制，以便为这种致残性疾病设计特定的治疗方法。

DESCRIPTION (provided by applicant): Pathogenic calcium crystals, including calcium pyrophosphate (CPPD) and basic calcium phosphate (BCP) crystals are common components of osteoarthritic joints. These crystals identify a subset of patients with unusually severe, rapidly progressive, arthritis. Yet, how crystals form in the normally unmineralized articular cartilage matrix remains unknown. Matrix vesicles are membrane-bound, chondrocyte-derived, extracellular organelles implicated in calcium crystal formation. Preliminary findings strongly suggest that the surrounding extracelllular matrix in cartilage clearly influences the matrix vesicle's ability to mineralize. There is ample precedence for an important interaction between matrix vesicles and their surrounding extracellular environment in growth plate cartilage. While dramatic changes in articular cartilage matrix occur in both osteoarthritis and with calcium crystal deposition, little is known about the interaction of extracellular matrix and matrix vesicles in articular cartilage. We hypothesize that interactions between matrix vesicles and extracellular matrix components strongly influence the ability of articular cartilage matrix vesicles to generate pathologic calcium crystals. In this proposal, we will will use porcine articular cartilage matrix vesicles in a gel-based calcification model to study I) the effects of type II collagen on articular cartilage matrix vesicle mineralization, II) the effects of large and small proteoglycans on articular cartilage matrix vesicle mineralization, and IN) the effects of the calcium binding proteins (osteopontin, SPARC, and matrix gla protein) on articular cartilage matrix vesicle mineralization. The ultimate goal of this work is to understand the pathogenesis of calcium crystal formation in articular cartilage, so that specific therapies for this disabling disease can be designed.