Collagen Cross-linking in Skeletal Aging and Disease

描述（由申请人提供）：我们正在研究胶原交联如何进化以适应人类骨骼，软骨和其他支持组织的独特功能。我们提出了一种结构，预测了骨胶原中吡咯交联的新化学和关键作用，并在软骨胶原中发现了一种以前未知的交联，精氨酸。我们提出并将寻求验证所有组织中纤维性胶原交联氧化成熟的统一理论。赖氨酸氧化酶的交联机制早在20世纪70年代就已被发现，但仍有许多未知之处。翻译后个体间胶原蛋白质量的差异，尤其是骨和软骨的交联化学差异，是骨质疏松性骨折和关节衰竭的潜在危险因素。它们是由累积的环境影响而不是直接的遗传基础造成的。我们正在通过使用先进的质谱蛋白质技术分析骨骼、软骨和其他骨骼组织胶原来实现这一目标。临床意义在于新的分子靶点有望满足骨质疏松症和骨关节炎的公共卫生挑战。骨骼组织在很大程度上依赖于高度专业化的胶原蛋白的交联，以获得其独特的强度、性能和寿命。因此，翻译的目的是寻找新的治疗分子靶点和基于尿胶原蛋白肽的非侵入性生物标志物，这些生物标志物可以指示患者的骨骼质量，关节软骨破裂率和其他骨骼健康指标。

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.