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）疗法之一。随着骨骼疾病在老龄化人口中变得越来越普遍，一个有待回答的问题是，像生姜这样的植物提取物是否可以作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和新骨形成的细胞途径变得不平衡，从而导致吸收超过形成，削弱或损害骨骼系统功能。类风湿性关节炎（RA）和骨质疏松是代谢性骨疾病，其中骨破坏是通过激活NF-kB （RANK）通路受体激活剂介导的，NF-kB （RANK）通路是骨吸收的最终共同途径。初步数据表明，表征良好的粗姜提取物能够通过抑制RANK通路抑制RA动物模型中关节周围骨的骨质流失。因此，我建议在代谢性骨病RA和绝经后骨质疏松两种模型中验证生姜作为骨保护剂的作用，并阐明生姜对骨的作用机制。在链球菌细胞壁（SCW）诱导的RA关节炎模型中，雌性Lewis大鼠将接受对照物或生姜提取物治疗，并监测关节炎骨质流失情况。分析终点包括双能x线吸收仪（DXA）测定骨密度（BMD）、骨转换血清标志物、骨组织形态测定法、基因阵列测定关节基因表达变化、实时反转录PCR验证生理重要基因表达变化、生姜调节基因蛋白水平定量。在绝经后骨质疏松症卵巢切除（OVX）模型中，雌性Sprague Dawley大鼠进行假手术或OVX，然后用对照物或生姜提取物治疗。除了先前命名的终点外，骨微计算机断层扫描（uCT）和机械骨强度也将在OVX研究中进行评估。最后，将测试粗姜提取物的特定亚组分（姜辣素和精油），以确定其在原代细胞培养中抑制破骨细胞分化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，它用于预防和治疗使人衰弱的代谢性骨病是一种令人兴奋的可能性。然而，缺乏严格的科学证据支持其用于这一目的。这里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.