Remodeling Suppression: Collagen Effects on Fracture Energy

描述（由申请人提供）：我们的目标是确定胶原交联（酶和非酶介导），胶原成熟度（α / β CTX）和晚期糖基化终产物（AGE）的积累在骨骼结构和物质能量吸收能力中的作用。目的1将确定使用目前用于治疗绝经后骨质疏松症或用于治疗佩吉特病的双膦酸盐剂量治疗2或3年后，骨中是否存在显著的AGE积累。AGE的积累将与韧性和归一化破坏能量相关。该Aim使用已经治疗和牺牲的狗，但提出了材料特性测量以及胶原交联和成熟分析，这些在我们最初的应用中没有提出。目的2将确定已知在骨骼中积累AGE的糖尿病大鼠是否表现出韧性和归一化能量的变化，这与我们的假设一致，即AGE积累与组织和结构水平上的能量减少有关。使用两种不同的AGE抑制剂将建立因果关系，并可能提供有关AGE积累机制的信息，因为抑制剂在反应周期的不同点起作用。目的3将允许我们在雌激素缺乏的动物模型（切除卵巢的大鼠）中建立AGE积累与机械特性改变之间的关系，这是一种已建立的绝经后骨质疏松症模型。使用AGE抑制剂将确定AGE积累与骨材料特性（韧性和归一化能量到失效）之间的因果关系，这可能与绝经后的情况比完整的狗更相关。作为NIH基础设施拨款的一部分，我们获得了一台新的Skyscan 1172微型ct，这将使我们能够评估小梁结构的变化，从而更好地表征小梁骨的特性。它还允许我们通过最小BV/TV平面规范化力学数据，以防止高密度骨区域加权而不会失败。我们的工作可以帮助解释双膦酸盐治疗导致韧性和归一化能量降低的原因，并确定是否有可能预防接受双膦酸盐治疗的患者发生这些变化。本提案的目的是确定胶原蛋白和晚期糖基化终产物的积累在骨的机械特性中所起的作用。这与理解发生在绝经后骨质疏松症和II型糖尿病中的骨质脆弱性有关。

DESCRIPTION (provided by applicant): Our objective is to determine the role that collagen cross-linking (both enzymatic- and non- enzymatically-mediated), collagen maturity (alpha/beta CTX), and the accumulation of advanced glycation end-products (AGE's) play in bone's structural and material energy absorption capacity. Aim 1 will determine whether there is a significant accumulation of AGE's in bone following 2 or 3 years treatment with doses of bisphosphonate currently used to treat postmenopausal osteoporosis, or those used to treat Paget's disease. AGE accumulation will be correlated to toughness and normalized energy to failure. This Aim uses dogs that have already been treated and sacrificed, but proposes material property measurements as well as analysis of collagen cross-linking and maturation that were not proposed in our original application. Aim 2 will determine whether diabetic rats, known to accumulate AGE's in bone, show changes in toughness and normalized energy to failure consistent with our hypothesis that AGE accumulation is associated with reduced energy to failure at the tissue and structural levels. Use of two different AGE inhibitors will establish cause and effect, and may provide information about the mechanism of AGE accumulation, as the inhibitors act at different points of the reaction cycle. Aim 3 will allow us to establish the relationship between AGE accumulation and altered mechanical properties in an estrogen-deficient animal model (ovariectomized rats), an established model for post-menopausal osteoporosis. Use of an AGE inhibitor will establish cause and effect between AGE accumulation and bone's material properties (toughness and normalized energy to failure) that may be more relevant to the post-menopausal situation than intact dogs. Acquisition of a new Skyscan 1172 micro-CT as part of an NIH infrastructure grant will allow us to assess changes in trabecular architecture to better characterize trabecular bone properties. It will also allow us to normalize the mechanical data by the plane of smallest BV/TV to prevent weighting by regions of bone with higher density that do not fail. Our work could help to explain the reason for the reduced toughness and normalized energy to failure found with bisphosphonate treatment, and to determine whether it is possible to prevent these changes in patients who are being treated with bisphosphonates. PUBLIC HEALTH NARRATIVE The objective of this proposal is to determine the role that collagen, and the accumulation of advanced glycation end-products, play in the mechanical properties of bone. This has relevance in understanding the fragility of bone that occurs in post-menopausal osteoporosis, and in Type II diabetes.