Osteocyte functions in osteoporosis of underused bone. Establishing a rat underuse model and its application to the analysis of drug effect

绝经后雌激素缺乏和活动减少(运动减退)都是老年妇女骨质疏松症发病的重要因素。为了独立比较这两个因素的贡献，我们建立了卵巢切除(OVX)和假手术大鼠的动物模型，它们被关在空间有限的笼子里。实验笼子限制站立和行走，而允许其他活动，如吃、喝和改变姿势。12周时处死大鼠，取股骨和胫骨进行外周定量计算机断层扫描(PQCT)、激光拉曼光谱、三点弯曲和组织病理学检查。尽管与Sham组相比，OVX组的代谢标记物、CTX和骨钙素水平显著升高，但骨强度和几何参数的结果仅在Sham组和限制组之间显示出显著差异。在受限制的大鼠胫骨皮质中，空骨细胞陷窝和骨小管硬化素染色均明显增加。不仅是骨变薄，骨髓间隙变窄还伴随着皮质内骨形成率的增加。在受限制的大鼠骨骼中，破骨细胞的活性与骨质疏松的病理并不一定相关。成骨细胞和破骨细胞活动的解偶联以及无序的骨细胞网络表明，在久坐的个体中，骨细胞控制皮质骨丢失的主要作用。通过显示甲状旁腺激素和步行之间的协同作用，该模型在评估药物对骨骼的影响方面被证明是有用的。皮质骨的不均匀向外伸展是由协同作用强度的局部差异所致。

Lack of estrogen after menopause and reduced activity (hypokinesis) are both important factors in the pathogenesis of osteoporosis in the elderly women. To compare the contribution of these two factors independently, we developed an animal model of ovariectomized (OVX) and sham-operated rats, which were housed in cages with limited space. The experimental cages restricted standing and walking, while allowing other activities such as eating, drinking and changing positions. After sacrificing rats at week 12, femora and tibia were examined with peripheral quantitative computed tomography (pQCT), laser Raman spectroscopy, three point bending, and histopathology. Although significantly elevated levels of metabolic markers, CTx, and osteocalcin were recorded in OVX groups compared to the Sham groups, results of bone strength as well as geometric parameters revealed significant differences only between Sham and Restricted groups. In the Restricted rat tibial cortices, both the number of empty osteocytic lacunae and lacuno-canalicular sclerostin staining were significantly increased. Not only was the bone thinner, narrowed marrow space was accompanied by the increased endocortical bone formation rate. Osteoclast activity was not necessarily associated with the osteoporotic pathology in the restrained rat bones. The uncoupling of osteoblastic and osteoclastic activities as well as the disorganized osteocyte network suggests a predominant role of osteocytic control over the cortical bone loss in the sedentary individuals. This model proved useful in evaluating the effect of drugs on bone by showing synergy between PTH and walking. The uneven outward extension of cortical bone was suggested from the local variation in the intensity of the synergistic effect.