Ginger Extracts in the Prevention of Metabolic Bone Disease

描述（由申请人提供）：草药和膳食补充剂是美国最常用的补充或替代医学（CAM）疗法。随着骨骼疾病在老龄化人口中变得更加普遍，一个有待回答的问题是，植物提取物，如生姜，是否可以成为治疗或预防常见骨骼疾病的有用膳食补充剂。在代谢性骨病中，调节旧骨的吸收或降解以及新骨形成的细胞途径变得不平衡，使得吸收超过形成，削弱或损害骨骼系统功能。风湿性关节炎（RA）和骨质疏松症是代谢性骨疾病，其中骨破坏是通过激活NF-κ B（RANK）途径的受体激活剂介导的，该途径是骨吸收的最终共同途径。初步数据表明，充分表征的生姜粗提取物能够通过抑制RANK途径抑制RA动物模型中关节周围骨的骨丢失。因此，我建议验证生姜作为骨保护剂的功效，并阐明生姜在两种代谢性骨疾病（RA和绝经后骨质疏松症）模型中对骨的影响机制。在用于RA的链球菌细胞壁（SCW）诱导的关节炎模型中，雌性刘易斯大鼠将用媒介物或生姜提取物处理，并监测关节炎性骨损失。分析的终点包括双能X射线骨密度仪（DXA）测定的骨矿物质密度（BMD）、骨转换的血清标志物、骨组织形态计量学、基因阵列测定的关节基因表达变化、实时逆转录PCR测定的生理学重要基因表达变化以及生姜调节基因蛋白水平的定量。在绝经后骨质疏松症的卵巢切除术（OVX）模型中，雌性Sprague道利大鼠将经历假手术或OVX，然后用载体或生姜提取物处理。除了先前命名的终点外，还将在OVX研究中评价骨显微计算机断层扫描（uCT）和骨机械强度。最后，将测试粗姜提取物的特定亚级分（姜辣素和精油）以确定它们在抑制原代细胞培养物中破骨细胞分化中的相对功效和作用机制。考虑到生姜目前作为膳食补充剂的可用性，使用生姜预防和治疗衰弱性代谢性骨病是一种令人兴奋的可能性。然而，缺乏支持其用于此目的的严格科学证据。本文提出的研究旨在解决这一重要的临床和公共卫生问题。

DESCRIPTION (provided by applicant): Herbs and dietary supplements are among the most commonly used complementary or alternative medical (CAM) therapies in the United States. As bone disorders become more prevalent in the aging population, a question that remains to be answered is whether botanical extracts, like ginger, could be useful dietary supplements in the treatment or prevention of common bone disorders. In metabolic bone disease, the cellular pathways that regulate the resorption or degradation of old bone and the formation of new bone become imbalanced such that resorption overtakes formation, weakening or impairing skeletal system function. Rheumatoid arthritis (RA) and osteoporosis are metabolic bone disorders in which bone destruction is mediated through activation of the receptor activator of NF-kB (RANK) pathway, the final common pathway for bone resorption. Preliminary data indicate that well characterized crude ginger extracts are able to inhibit bone loss in peri-articular bone in an animal model of RA through the inhibition of the RANK pathway. I therefore propose to verify ginger's efficacy as a bone-protective agent and elucidate the mechanism of ginger's effect on bone in two models of metabolic bone disease, RA and postmenopausal osteoporosis. In the streptococcal cell wall (SCW)-induced arthritis model for RA, female Lewis rats will be treated with vehicle or ginger extracts, and monitored for arthritic bone loss. Endpoints of analysis include bone mineral density (BMD) by dual energy x-ray absorptometry (DXA), serum markers for bone turnover, bone histomorphometry, changes in articular gene expression by gene array, verification of changes in expression of physiologically important genes by real-time reverse transcription PCR, and quantification of protein levels of ginger-regulated genes. In the ovariectomy (OVX) model of postmenopausal osteoporosis, female Sprague Dawley rats will undergo sham-operation or OVX, and then be treated with either vehicle or ginger extracts. In addition to previously named endpoints, bone micro-computed tomography (uCT) and mechanical bone strength will also be evaluated in the OVX study. Finally, specific sub-fractions of crude ginger extract (gingerols and essential oils) will be tested to determine their relative efficacy and mechanism of action in inhibiting osteoclast differentiation in a primary cell culture. The use of ginger for the prevention and treatment of debilitating metabolic bone disease is an exciting possibility considering its current availability as a dietary supplement. However, rigorous scientific evidence supporting its use for this purpose is lacking. The studies proposed here intend to address this important clinical and public health issue.