Bone marrow blood vessel location and blood flow with PTH and anti-VEGF

描述(申请人提供)：骨病的病因是多因素的。例如，有证据表明，随着年龄的增长，骨灌注量减少、骨小动脉功能和骨量减少之间存在明显的关系，这是一个全球健康问题。因此，也许药物干预可以针对非骨骼组织。甲状旁腺激素(PTH)增加骨量，但也调节血管功能。间歇给药时，甲状旁腺素可缩短血管和骨形成部位(即类骨表面)之间的距离，并增强股骨主要滋养动脉(PNA)的血管扩张作用，PNA是血液流向长骨的主要管道。有趣的是，联合应用抗血管内皮生长因子抗体(Ab)可以阻止骨血管的移位，抑制增强的血管扩张功能，并钝化与甲状旁腺激素相关的骨积累；强调了血管内皮生长因子信号的重要性。骨血管的空间位置对骨形成至关重要。由于在甲状旁腺激素诱导的骨积累条件下，血管-类骨质分离减少，可能这种分离随着年龄的增加而增加，从而导致骨丢失。因此，年龄相关性骨质疏松症的部分病因可能源于骨血流减少和血管-骨样物质分离增加。这项建议的目的是研究间歇性甲状旁腺素给药是否会减少假定的与年龄相关的血管-骨样物质分离，并恢复与年龄相关的骨骼灌注量的下降。第二个目标是确定这些血管改变是否受血管内皮生长因子的调节。对雄性Fischer-344大鼠进行分析：1)青年，2)老年，3)青年+甲状旁腺激素，4)老年+甲状旁腺激素，5)青年+甲状旁腺激素+抗血管内皮生长因子抗体，6)老年+甲状旁腺激素+抗血管内皮生长因子抗体。Micro-CT和骨组织形态计量学将评估骨的微结构、骨的静态和动态特性、骨血管密度和血管-骨样分离。最后，体内骨血流测量将通过向循环中注射放射性标记微球来进行分析。这些发现将提供有关骨血管的空间分布随年龄、骨重塑、质量和药物干预的函数的新信息。此外，在观察到甲状旁腺素诱导的骨积累的血管机制的同时，可以观察到骨微结构和骨的静态和动态特性的改变。拟议的研究将从机械上评估血管内皮生长因子的作用，并为未来研究此类药物对骨细胞代谢和血管功能的同时使用奠定基础。

DESCRIPTION (provided by applicant): The etiologies of bone disease are multifactorial. For example, evidence indicates a clear relation between both reduced bone perfusion and bone arteriolar function and diminished bone mass with aging, a global health concern. Thus, perhaps pharmaceutical interventions can be directed toward non-skeletal tissues. Parathyroid hormone (PTH) augments bone mass; however, it is also modulates vascular function. When given intermittently, PTH reduces the distance between blood vessels and sites of bone formation (i.e., osteoid surfaces) and it augments vasodilation of the femoral principal nutrient artery (PNA), the primary conduit for blood flow to long bones. Interestingly, co-administration of an anti-vascular endothelial growth factor (VEGF) antibody (Ab) prevented the relocation of bone blood vessels, inhibited the enhanced vasodilator function and blunted the bone accrual associated with PTH; highlighting the importance of VEGF signaling. The spatial location of bone blood vessels is vital for bone formation. Since vascular- osteoid separation decreased under conditions of PTH-induced bone accrual, perhaps this separation increases as a function of age; contributing to bone loss. Thus, age-related osteoporosis may derive a portion of its etiology from reduced bone blood flow and increased vascular-osteoid separation. The goals of this proposal are to examine whether intermittent PTH administration will diminish the presumed age-related augmented vascular-osteoid separation and restore the age-related declines in skeletal perfusion. A secondary goal is to determine whether these vascular alterations are regulated by VEGF. Analyses will be made among male Fischer-344 rats: 1) young, 2) old, 3) young+PTH, 4) old+PTH, 5) young+PTH+anti-VEGF Ab and 6) old+PTH+anti-VEGF Ab. Micro-CT and bone histomorphometry will assess bone microarchitecture, bone static and dynamic properties, bone vascular density and vascular-osteoid separation. Finally, in vivo bone blood flow measurements will be analyzed by injection of radiolabeled microspheres into the circulation. Findings will provide novel information concerning the spatial distribution of the bon blood vessels as a function of age, bone remodeling and mass and drug intervention. Further, the presumed vascular mechanisms of PTH-induced bone accrual can be observed concurrent to alterations in bone microarchitectural and bone static and dynamic properties. The proposed studies will mechanistically assess the role of VEGF and lay the groundwork for future studies examining the use of such pharmacological agents on bone cellular metabolism and vascular function concurrently.