Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Göttingen , Göttingen , Germany.
Department of Neurosurgery, University Medical Center Göttingen , Göttingen , Germany.
J Appl Physiol (1985). 2018 Jan 1;124(1):118-130. doi: 10.1152/japplphysiol.01126.2016. Epub 2017 Aug 31.
Estrogen deficiency and aging are associated with osteoporosis, impaired bone healing, and lower cognitive performance. Close functional and physical connections occur between bone and the central nervous system. An anti-inflammatory drug, zileuton (which is an inhibitor of arachidonate 5-lipoxygenase), is known to have a positive effect on bone tissue repair and brain ischemia. We studied the effect of zileuton on osteopenic bone and its healing and on the genes considered to be crucial for the cross talks between bone and brain. Three-month-old Sprague-Dawley rats were ovariectomized or left untreated. After 8 wk, bilateral metaphyseal tibia osteotomy with plate osteosynthesis was performed in all rats. Ovariectomized rats were fed with food containing zileuton (1, 10, or 100 mg/kg body wt) for 5 wk. In tibiae, bone volume, callus and cortical volume, and gene expression of osteocalcin and alkaline phosphatase were enhanced by zileuton (10 or 100 mg); biomechanical properties and bone density were not changed. In femur, zileuton enlarged cortical volume distal and trabecular volume proximal, decreasing their density. The expression level of brain Sema3a, known to regulate bone mass positively, was downregulated after ovariectomy. In contrast, bone Sema4d, a negative regulator of bone mass, was upregulated in the tibia callus after ovariectomy, whereas zileuton treatment (10 or 100 mg) resulted in reverse effects. Here, we describe for the first time the expression of Rbbp4 mRNA and its increase in tibia after ovariectomy. Zileuton caused downregulation of Rbbp4 in the hippocampus and had an effect on bone healing, changed the expression of genes involved in cross talk between bones and brain, and may be a potent drug for further examination in estrogen deficiency-related dysfunction(s). NEW & NOTEWORTHY Zileuton, a 5-lipoxygenase inhibitor, increased bone volume, callus and cortical volume in osteotomized tibia, and trabecular and cortical volume in femur. Although the expression of Sema3a (positively regulating bone mass) in brain was downregulated and Sema4d (negatively regulating bone mass) was upregulated in tibia callus after ovariectomy, zileuton could counteract these effects. Rbbp4 (involved in age-related memory loss) was increased in tibia callus after ovariectomy.
雌激素缺乏和衰老与骨质疏松症、骨愈合受损和认知能力下降有关。骨骼和中枢神经系统之间存在密切的功能和物理联系。一种抗炎药物齐留通（一种花生四烯酸 5-脂氧合酶抑制剂）已知对骨组织修复和脑缺血有积极作用。我们研究了齐留通对骨质疏松骨及其愈合的影响，以及对被认为是骨骼和大脑之间交叉对话关键的基因的影响。3 月龄 Sprague-Dawley 大鼠行卵巢切除术或不做处理。8 周后，所有大鼠均行双侧胫骨干骺端截骨伴钢板内固定术。卵巢切除大鼠用含齐留通（1、10 或 100mg/kg 体重）的食物喂养 5 周。胫骨中，骨体积、骨痂和皮质体积以及骨钙素和碱性磷酸酶的基因表达均被齐留通（10 或 100mg）增强；生物力学特性和骨密度无变化。股骨中，齐留通增加了远端皮质体积和近端松质骨体积，降低了其密度。脑 Sema3a 的表达水平降低，已知其正向调节骨量，卵巢切除后降低。相反，骨 Sema4d，骨量的负调节因子，在卵巢切除后的胫骨骨痂中上调，而齐留通（10 或 100mg）治疗则产生相反的效果。在这里，我们首次描述了 Rbbp4mRNA 的表达及其在卵巢切除后胫骨中的增加。齐留通使 Hippocampus 中的 Rbbp4 下调，并对骨愈合产生影响，改变了涉及骨骼和大脑之间交叉对话的基因的表达，可能是一种治疗雌激素缺乏相关功能障碍的有效药物。新的和值得注意的是，5-脂氧合酶抑制剂齐留通增加了胫骨骨折部位的骨体积、骨痂和皮质体积，以及股骨的松质骨和皮质体积。尽管脑 Sema3a（正向调节骨量）的表达在卵巢切除后的胫骨骨痂中下调，而 Sema4d（负向调节骨量）上调，但齐留通可以抵消这些作用。Rbbp4（参与与年龄相关的记忆丧失）在卵巢切除后的胫骨骨痂中增加。
