Collagen Cross-linking in Skeletal Aging and Disease

描述(申请人提供)：我们正在研究胶原交联物是如何进化的，以适应人类骨骼、软骨和其他支持组织的独特功能。我们提出了一种结构，它预测了骨胶原中吡咯交联物的一种新的化学和关键作用，并在软骨胶原中发现了一种以前未知的交联物精氨酸。我们建议并将寻求验证所有组织的纤维胶原蛋白中的交联物的氧化成熟的统一理论。虽然赖氨酰氧化酶的交联机制在20世纪70年代就已被发现，但仍有许多未知之处。翻译后个体之间胶原质量的差异，特别是骨和软骨的交联化学，是骨质疏松性骨折和关节衰竭的潜在危险因素。它们是累积的环境影响的结果，而不是直接的遗传基础。我们正在通过使用先进的质谱学蛋白质技术对骨、软骨和其他骨骼组织胶原蛋白进行分析来实现这一点。临床意义在于，在努力应对骨质疏松症和骨性关节炎的公共卫生挑战方面，有望开发出新的分子靶点。骨骼组织因其独特的强度、特性和寿命而严重依赖高度专业化的胶原蛋白的交联性。因此，翻译的目标是寻找新的治疗分子靶点和基于尿胶原肽的非侵入性生物标记物，这些标记物可以指示患者的骨骼质量、关节软骨破损率和其他骨骼健康指标。 与公共健康相关：利用蛋白质质谱仪的力量，目标是完成对不同骨骼胶原蛋白如何共价交联的基本科学理解。随着年龄的增长，骨胶原交联性的质量差异，可能与骨质疏松性骨折的风险无关，与骨密度无关，这是特别值得关注的。在进行基础组织研究的同时，尿液中的胶原蛋白片段也被用类似的方法进行检测，作为患者骨骼和关节健康的潜在非侵入性生物标志物。

DESCRIPTION (provided by applicant): We are studying how collagen cross-links have evolved to adapt human bone, cartilage and other supporting tissues for their distinctive functions. We have raised the structure which predicts a novel chemistry and critical role for pyrrole cross-links in bone collagen and identified a previously unknown cross-link, arginoline, in cartilage collagen. We propose and will seek to validate a unified theory of oxidative maturation for cross-links in the fibrillar collagens of all tissues. Though the lysyl oxidase cross-linking mechanism was discovered in the 1970s, much is still unknown. Post-translational differences in collagen quality between individuals, notably in the cross-linking chemistry of bone and cartilages, are potential risk factors for osteoporotic fracture and joint failure. They result from cumulative environmental influences rather than a direct genetic basis. We are pursuing this through analyses of bone, cartilage and other skeletal tissue collagens using advanced mass spectrometric protein techniques. The clinical significance is the promise of new molecular targets in the effort to meet the public health challenges of osteoporosis and osteoarthritis. Skeletal tissues depend heavily on the cross-linking of highly specialized collagens for their unique strengths, properties and longevity. The translational aim, therefore, is to seek new molecular targets for therapy and non- invasive biomarkers based on urinary collagen peptides that can index a patient's bone quality, joint cartilage breakdown rate and other measures of skeletal health. PUBLIC HEALTH RELEVANCE: Using the power of protein mass spectrometry the goal is to complete a basic scientific understanding of how different skeletal collagens are covalently cross-linked. Qualitative differences in bone collagen cross-linking that develop with age and may to be linked to risk of osteoporotic fracture independent of bone density are of particular interest. In parallel with basic tissue studies, collagen fragments in urine are being examined by similar methods as potential non-invasive biomarkers of a patient's bone and joint health.