Remodeling Suppression: Collagen Effects on Fracture Energy

描述(申请人提供)：我们的目标是确定胶原交联性(酶和非酶介导的)、胶原成熟度(α/βCTX)和晚期糖基化终末产物(AGE)的积累在骨骼的结构和材料能量吸收能力中所起的作用。目的1将确定目前用于治疗绝经后骨质疏松症的双膦酸类药物或用于治疗Paget病的药物治疗2或3年后，AGE在骨骼中是否有显著积累。年龄积累将与韧性相关，归一化能量与失效相关。这一目标使用的是已经接受治疗和牺牲的狗，但提出了材料特性测量以及胶原交联度和成熟度的分析，这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失败能量的变化，这与我们的假设一致，即AGE积累与组织和结构水平上的失败能量减少有关。使用两种不同的AGE抑制剂将确定因果关系，并可能提供有关AGE累积机制的信息，因为这两种抑制剂在反应周期的不同点起作用。目的3将使我们能够在雌激素缺乏的动物模型(去卵巢的大鼠)中建立绝经后骨质疏松症的动物模型中年龄积累和机械性能改变之间的关系。使用年龄抑制剂将建立年龄积累和骨骼材料特性(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。作为美国国立卫生研究院基础设施拨款的一部分，购买新的Skyscan1172Micro-CT将使我们能够评估骨小梁结构的变化，以更好地表征骨小梁特性。它还将允许我们通过最小BV/TV平面来归一化力学数据，以防止按不失败的高密度骨区域进行加权。我们的工作可以帮助解释双磷酸盐治疗中发现的韧性和归一化能量下降到失败的原因，并确定是否有可能预防正在接受双膦酸盐治疗的患者的这些变化。公共卫生叙述这项建议的目的是确定胶原蛋白和晚期糖基化终产物的积累在骨骼的机械性能中所起的作用。这对于了解绝经后骨质疏松症和II型糖尿病患者的骨脆性有重要意义。

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.