OSTEOGENIC AND ANGIOGENIC RESPONSE TO SKELETAL LOADING

描述（由申请方提供）：非软骨内骨形成（骨生成）以板层骨或编织骨的形式发生。板层骨在正常建模和重塑过程中形成，而编织骨作为损伤反应的一部分形成（例如，骨折愈合、牵引成骨、疲劳/应力骨折）。关于是什么导致相同类型的细胞（成骨细胞）在一种情况下直接产生板层骨，在另一种情况下直接产生编织骨，我们知之甚少。编织骨的一个优点是它可以快速增加骨宽度和惯性矩，从而快速恢复全骨刚度和强度。如果能够更好地理解非软骨内编织骨形成的途径，可能会发现治疗低骨量和低强度疾病的新策略。最近的研究表明，一个快速的编织骨反应发生后，单回合的破坏性疲劳负荷。根据观察结果，新血管形成（血管生成）也发生在骨疲劳负荷后，我们假设血管生成反应可能会影响成骨反应的性质，即编织与层状。我们的长期目标是确定机械负荷后导致快速非软骨内骨形成的机械生物学途径。我们假设：（1）机械负荷诱导的编织骨形成是对结构损伤的反应，而不是对循环变形的反应;（2）对破坏性疲劳负荷的成骨反应取决于血管生成反应的活力。使用大鼠尺骨负荷模型，在具体目标1中，我们将：（A）确定对疲劳的成骨反应（即，动态）载荷作为结构损伤水平的函数;（B）确定对蠕变的成骨反应（即，静态）载荷作为结构损伤水平的函数;以及（C）将骨形成模式与骨应变的有限元预测模式相关联。在具体目标2中，我们将：（A）评估损伤性疲劳负荷后骨血管系统的变化;（B）评估重要成骨细胞（例如，BMP-2）和血管生成因子（例如，VEGF）;和（C）评估抗血管生成化合物在破坏性疲劳负荷后阻断编织骨形成的能力。总之，这些研究将建立重要的机械和血管生成因子，介导板层骨与编织骨形成的不同过程。它们将扩展我们对骨骼应力损伤（疲劳骨折）的成骨反应的理解，并将作为未来开发快速骨形成以增强弱骨或受损骨的新策略的基础。

DESCRIPTION (provided by applicant): Non-endochondral bone formation (osteogenesis) occurs either as lamellar or woven bone. Lamellar bone forms during normal modeling and remodeling, whereas woven bone forms as part of an injury response (e.g., fracture healing, distraction osteogenesis, fatigue/stress fractures). Little is known about what leads the same cell type (the osteoblast) to directly produce lamellar bone in one case and woven bone in another. An advantage of woven bone is that it can quickly increase bone width and moment of inertia, leading to rapid restoration of whole-bone stiffness and strength. If the pathway(s) of non-endochondral woven bone formation could be better understood, it may lead to the discovery of novel strategies for treating disorders of low bone mass and strength. Recent work has demonstrated that a rapid woven bone response occurs after a single bout of damaging fatigue loading. In light of observations that new blood vessel formation (angiogenesis) also occurs after fatigue loading of bone, we hypothesize that the angiogenic response may influence the nature of the osteogenic response, i.e. woven versus lamellar. Our long-term goal is to determine the mechano-biological pathway that leads to rapid non-endochondral bone formation after mechanical loading. We hypothesize: (1) mechanical loading-induced woven bone formation is a response to structural damage rather than a response to cyclic deformation; and (2) the osteogenic response to damaging fatigue loading is dependent on the vigor of the angiogenic response. Using the rat ulnar loading model, in Specific Aim 1 we will: (A) determine the osteogenic response to fatigue (i.e., dynamic) loading as a function of the level of structural damage; (B) determine the osteogenic response to creep (i.e., static) loading as a function of the level of structural damage; and (C) correlate patterns of bone formation with finite element-predicted patterns of bone strain. In Specific Aim 2, we will: (A) assess changes in bone vasculature following damaging fatigue loading; (B) assess the spatial pattern of expression of important osteogenic (e.g., BMP-2) and angiogenic factors (e.g., VEGF); and (C) assess the ability of anti-angiogenic compounds to block woven bone formation after damaging fatigue loading. Taken together, these studies will establish important mechanical and angiogenic factors that mediate the distinct processes of lamellar versus woven bone formation. They will extend our understanding of the osteogenic response to skeletal stress injuries (fatigue fractures) and will serve as a basis for future development of novel strategies for rapid bone formation to augment weak or damaged bones.