模拟微重力环境对骨代谢的影响

骨是一种多功能器官,重力或机械力刺激对动物及人类骨骼系统的生长、发育及功能维持均起着非常重要的作用,因此缺乏重力或机械刺激会造成明显的骨骼变化.早在上世纪六十年代人们就发现太空微重力环境造成宇航员骨代谢的变化和快速骨质丢失,太空微重力环境可以导致骨吸收增强和骨形成的抑制作用,这种骨代谢的失平衡造成的骨质丢失,但导致骨代谢不平衡的原因尚不清楚.人长期卧床和鼠尾悬吊使负重骨处于一种失负荷状态,是地面上常用的模拟微重力模型,两种模型均表现为和太空环境相似的骨代谢改变以及骨质的快速丢失,鼠尾悬吊模型提供的骨形态测量学结果 也表明骨质丢失、骨吸收的增强和骨形成功能的降低.骨吸收和骨形成分别由破骨细胞和成骨细胞完成,细胞分子学水平的研究表明微重力环境抑制成骨细胞的增殖,促使细胞凋亡,降低成骨细胞转录因子和特异性因子的表达,抑制成骨细胞的分化,并通过增加RANKL/OPG的比例促进破骨细胞的形成.微重力环境成骨细胞功能的降低和破骨细胞功能的增强所致的骨代谢的不平衡导致了骨质丢失,因此恢复平衡的骨代谢可能是防治微重力环境骨质丢失的必要手段.     

微重力引起的骨质丢失研究进展

人类对太空的探索日益频繁,然而太空微重力会引起航天员骨质丢失,对航天员的健康造成损害。因此,有研究者通过航天实验及模拟微重力实验研究微重力下骨质丢失的发生机制及解决措施。微重力会引起成骨细胞和破骨细胞代谢活动改变,并引起机体对钙离子新陈代谢的改变。航天微重力导致的骨质丢失是微重力和太空射线共同作用的结果。本文将对微重力所致骨质丢失的发生机制和治疗对策加以概述。     

微重力对MC3T3-E1前成骨细胞增殖、分化影响的研究进展

宇航员在太空飞行中经历的微重力导致人体发生严重生理变化,其中包括头部液体移位、液体和电解质流失、肌肉质量减少、空间晕动病、贫血、免疫反应降低以及骨质流失等,骨质流失是这些问题中最重要的问题之一,其严重程度似乎与飞行持续时间有关。航天飞行期间宇航员每月损失1%~2%的骨量,这种损失很大程度上是由于促进骨形成的成骨细胞标志物的减少引起,导致骨形成明显减少和骨吸收增加的潜在分子机制尚不清楚。研究证明微重力条件下骨形成减少与骨成熟标志物的减少,细胞骨架的改变,凋亡和自噬的增加以及其他相关蛋白及基因的变化有关,这也间接表明了微重力下骨质流失是一个复杂的生理过程。本文对近年来模拟微重力条件下MC3T3-E1前成骨细胞增殖和分化影响的研究进展作一综述,以期为航空航天条件下骨丢失的预防和治疗提供一定的理论基础。     

微重力对骨稳态调节作用的相关研究进展

骨稳态的维持需要破骨细胞、成骨细胞和骨细胞的信号传导以及干细胞的增殖分化参与。微重力导致机械载荷减少进而改变骨稳态内细胞代谢。本综述介绍微重力对骨稳态的调节关系,以及其作用机制。微重力使成骨细胞增殖分化延迟,破骨细胞吸收增强,骨细胞溶解,巨噬细胞介导免疫炎症因子调控成骨和破骨平衡。骨骼系统的调节机制复杂,各细胞类型相互影响,多信号通路交叉作用。未来还需进一步探索骨稳态失调引起的骨质疏松的治疗靶点。     

微重力状态下骨量丢失对抗措施的研究进展

微重力状态下骨量丢失不同于老年性骨质疏松,是一种局部力学信号转导起主导作用、并受多层次调节的复杂变化过程,是一种特殊的废用性骨质疏松和继发性骨质疏松。长期的微重力环境,骨矿盐的持续丢失是航天飞行中人类所面临的严重生理反应之一,也是妨碍人类长期太空停留和探索外星球的主要障碍之一。目前微重力环境下骨量丢失的对抗措施主要有:物理对抗、营养、药物、细胞因子与基因治疗。航天飞行中,阻力锻炼、振动、人工重力等物理对抗措施的研究较为成熟;营养措施中着重阐述维生素、矿物质、蛋白质、Ω-3脂肪酸对骨代谢的作用,各种营养物质的具体摄入量仍有待规范;药物措施中双膦酸盐的使用基本得到广泛认可,其他药物的应用仍需要继续人体探索;细胞因子与基因的研究目前仍限于应用细胞进行研究。高级阻力训练系统(ARED)联合营养(部分联合双膦酸盐)是目前公认有效的对抗航天飞行中骨量丢失的措施。本文将详细阐述以上各个方面国内外的进展及争议,以及探讨未来微重力状态下骨量丢失的对抗措施的发展方向。     

活性氧影响骨重建在骨质疏松发病中的作用

骨重建是成年骨组织改建的主要形式，同时受生物力学因素和非生物力学因素调控。机体内活性氧产生和清除失衡会造成氧化应激,在此状态下活性氧作为非生物力学因素参与调控的骨重建与骨质疏松的发生有密切关系。活性氧损伤骨细胞转导力学信号的能力，上调骨重建阈值，导致骨组织已经习惯的力学刺激不足以维持骨量，而发生失用型骨重建。同时，在更新骨质和修复微损伤时，活性氧抑制成骨细胞分化和骨形成，促进破骨细胞形成和骨吸收，导致负性骨重建。总的效应是骨量逐年丢失，伴随骨结构逐渐退行性变，骨质疏松随年龄的增加而加重。     

胰岛素抵抗致骨强度下降的机制研究

胰岛素抵抗是2型糖尿病重要的发病机制之一，随着胰岛素抵抗程度的增加，骨成长和骨重塑过程变化导致骨折风险增加。在胰岛素抵抗的患者中，并不完全表现为骨密度减少的骨质疏松症，也可能表现为正常或者高骨密度，导致2型糖尿病患者骨密度未见明显异常而骨折风险增加，这可能是由于成骨细胞和破骨细胞对胰岛素敏感度降低或者胰岛素抵抗导致的低度炎症、维生素D降低、骨细胞间隙矿化等因素影响骨形成和骨吸收的平衡。胰岛素抵抗导致骨强度下降的机制有待充分阐明以期其指导胰岛素抵抗患者的抗骨质疏松治疗。     

姜黄素治疗骨质疏松的研究进展

姜黄素在骨质疏松的防治中具有显著的作用,可通过抑制骨髓间充质干细胞的凋亡与成脂分化,促进骨髓间充质干细胞增殖与成骨分化,促进成骨细胞增殖与分化,增强成骨细胞活力,减少成骨细胞凋亡,降低破骨细胞活性,诱导破骨细胞凋亡,抑制破骨细胞的生成、分化与骨吸收,改善骨代谢与骨小梁微观结构,减少骨量的丢失,增加骨骼的强度。但目前有关姜黄素治疗骨质疏松基本处于实验室研究阶段,姜黄素投入抗骨质疏松的临床使用仍需进一步以及更多的基础实验研究证实。综述姜黄素治疗骨质疏松的相关机制与进展,以期为姜黄素治疗骨质疏松在基础医学研究、药物临床应用以及新药物的开发等提供参考。     

骨质疏松症动物模型研究进展

骨质疏松症(osteoporosis,OP)是一种临床上常见的以骨量减少和骨组织微观结构破坏为特点,从而导致骨脆性增加、易于发生骨折的全身代谢性疾病。随着人口老龄化进程的加速,骨质疏松症尤其是绝经后骨质疏松症的发生率逐渐上升,骨质疏松症在医学上和社会性的影响逐渐加深。人类骨质疏松症主要有糖皮质激素相关型、绝经后骨质疏松症以及失用型、老年性骨质疏松症几种类型。糖皮质激素相关型骨质疏松症动物模型利用糖皮质激素诱导建立,其降低成骨细胞的活性、刺激破骨细胞,从而减少骨形成、增加骨吸收。利用去势法建立绝经后骨质疏松动物模型,其原理是雌激素减少致使骨吸收增加、新骨形成降低,最终达到骨量减少的目的。雌激素受体α诱导破骨细胞凋亡,但是阻碍成骨细胞功能的机制目前尚不明确。SAM-P6(Senescence-accelerated mouse-P6)是一种衰老加速的小鼠,骨丢失随年龄增长而增加,适用于老年型骨质疏松动物模型。失用型骨质疏松动物模型常见的建模方法有坐骨神经切除法、悬吊法等,机体长期处于无重力负荷状态,使得破骨细胞活性相对增加,导致骨量丢失。笔者就不同种类动物作为骨质疏松症研究模型的优缺点、绝经后骨质疏松症动物模型中对不同部位骨骼的影响作简要概述。     

雷奈酸锶在模拟微重力环境对成骨细胞增殖功能的影响

目的 观察新型的抗骨质疏松药雷奈酸锶在模拟微重力环境下对成骨细胞增殖功能的影响.方法 利用沿水平轴连续回转(30 r/min)细胞培养系统模拟微重力环境,使用MTT比色法或台盼兰染色、细胞计数法观察小鼠成骨样细胞MC3T3-E1的增殖情况.结果 模拟微重力环境可以降低MC3T3-E1增殖功能,雷奈酸锶在模拟微重力环境可以增强MC3T3-E1增殖功能.结论 在模拟微重力环境下雷奈酸锶对成骨细胞增殖功能具有保护作用,为雷奈酸锶治疗微重力环境骨量丢失提供了理论和实验证据.     

航天员中长期飞行骨骼健康管理研究现状

骨质疏松是航天员太空飞行后面临的主要健康威胁之一。中长期飞行会对航天员骨骼健康带来明显影响。1个月的太空飞行骨丢失量相当于绝经后妇女1年的丢失量。目前对失重后骨质疏松的研究和评估方法主要是骨密度、定量CT、有限元分析和生物力学测定。骨丢失的对抗性措施和治疗老年性骨质疏松症类似,主要包括运动锻炼、营养补充和药物治疗等。本文概述了国内外这一领域的研究现状、骨骼健康评估方法、常用对抗骨丢失应对措施,尝试提出对我国航天员中长期飞行骨骼健康管理的初步建议。     

Effects of microgravity on osteoclast bone resorption and osteoblast cytoskeletal organization and adhesion

Exposure to microgravity has been associated with several physiological changes in astronauts, including an osteoporosis-like loss in bone mass. Despite many in vivo and in vitro studies in both microgravity and simulated microgravity conditions, the mechanism for bone loss is still not clear. The lack of weight-bearing forces makes microgravity an ideal physical stimulus to assess bone cell responses. In this work, we conduct a unique investigation of the effects of microgravity on bone-producing osteoblasts and, in parallel, on bone-resorbing osteoclasts. An increase in total number of discrete resorption pits is observed in osteoclasts that experienced microgravity versus ground controls. We further show that osteoblasts exposed to 5 days of microgravity have shorter and wavier microtubules (MTs), smaller and fewer focal adhesions, and thinner cortical actin and stress fibers. Space-flown osteoblasts present extended cell shapes as well as significantly more disrupted and often fragmented or condensed nuclei. The absence of gravitational forces therefore causes both an increase in bone resorption by osteoclasts, and a decrease in osteoblast cellular integrity. The observed effects on both major bone cell types likely accelerate bone loss in microgravity environments, and additionally offer a potential explanation to the development of disuse osteoporosis on Earth.     

失重性骨质疏松的发生机制及中药对其防治作用的研究进展

太空中由于重力消失,体液分布紊乱,会导致承重骨的肌肉发生进行性萎缩,骨骼所受到的应力刺激减少或消失,成骨细胞增殖障碍,从而导致了失重骨质疏松的发生。与其他骨质疏松不同的是该类型的骨质疏松的发生和发展具有一定的部位选择性,且返回地面后恢复比较困难。常规干预措施如药物、体育锻炼、机械刺激等虽然对缓解骨丢失起到一定的疗效,但也存在着一定弊端。中医认为"肾主骨生髓",主张从肾论治,收到了满意的疗效。在地面实验中,研究人员也发现采用补肾中药可以有效促进成骨细胞增殖,从而对抗模拟失重所造成的骨量丢失。因此本文拟对失重骨质疏松的发生机制及中医药在对抗失重骨质疏中的应用进行概述。     

Reaction of the circulatory system to injury and regeneration

The anatomy of the bone blood supply is well known. Techniques to measure bone blood flow are available, but no accurate method is available for clinical use. Ion movement from the capillary to the matrix is by diffusion, and efflux appears to be controlled by a concentration-dependent binding mechanism in the extravascular space of bone. The resistance vessels of bone are regulated by local, neural, and humoral factors. Fractures of long bone provoke a decrease in blood flow followed by a large increase in blood flow driven by metabolic demand. Fractures heal by coordinated formation of new bone, which is a combination of interstitial and surface remodeling. Age affects bone remodeling. Fixation of an experimental fracture may modify blood flow as well as bone remodeling. Fluid fluxes in bone may produce streaming potentials that in turn stimulate the osteoblasts to form new bone.     

Central control of bone formation

Vertebrates constantly remodel bone to maintain a constant bone mass. Bone remodeling comprises two phases: bone resorption by the osteoclasts followed by bone formation by the osteoblasts. Although the prevailing view about the control of bone remodeling is that it is an autocrine/paracrine phenomenon, the bone resorption arm of bone remodeling is under a tight endocrine control. To date little is known about the regulation of bone formation. We took the observations that gonadal failure favors bone loss and obesity protects from it as an indication that bone mass, body weight, and reproduction could be regulated by the same hormone(s). Leptin is one of these hormones. Leptin inhibits bone formation by the osteoblasts. This function is dominant, and leptin deficiency results in a high bone mass phenotype despite the hypogonadism characterizing these animals. Genetic biochemical and physiological studies demonstrate that leptin inhibits bone formation following its binding to its receptor in the hypothalamus. These results are the first evience that bone remodeling is a hypothalamic process; they imply necessarily that osteoporosis, the most frequent bone remodeling disease, is partly at least a hypothalamic disease. This finding also has therapeutic implications. Received: December 6, 2000     

Bone remodeling is regulated by inner ear vestibular signals

Bone remodeling allows the conservation of normal bone mass despite constant changes in internal and external environments. The adaptation of the skeleton to these various stimuli leads credence to the notion that bone remodeling is a true homeostatic function, and as such is under the control of specific centers in the central nervous system (CNS). Hypothalamic and brainstem centers, as well as the sympathetic nervous system (SNS), have been identified as regulators of bone remodeling. However, the nature of the afferent CNS stimuli that may modulate CNS centers involved in the control of bone remodeling, with the exception of leptin, remains unclear. Based on the partial efficacy of exercise and mechanical stimulation regimens to prevent microgravity‐induced bone loss and the known alterations in vestibular functions associated with space flights, we hypothesized that inner ear vestibular signals may contribute to the regulation of bone remodeling. Using an established model of bilateral vestibular lesions and microtomographic and histomorphometric bone analyses, we show here that induction of bilateral vestibular lesion in rats generates significant bone loss, which is restricted to weight‐bearing bones and associated with a significant reduction in bone formation, as observed in rats under microgravity conditions. Importantly, this bone loss was not associated with reduced locomotor activity or metabolic abnormalities, was accompanied with molecular signs of increased sympathetic outflow, and could be prevented by the β‐blocker propranolol. Collectively, these data suggest that the homeostatic process of bone remodeling has a vestibulosympathetic regulatory component and that vestibular system pathologies might be accompanied by bone fragility. © 2013 American Society for Bone and Mineral Research.     

Stochastic simulation of vertebral trabecular bone remodeling

Bone remodeling changes bone mass, architecture, and thereby bone strength, during normal aging. These changes seem to be accelerated during the menopause. Several therapeutic agents have been used in order to delay the onset of the menopause-related changes. The effects of these agents on the remodeling process have been determined histomorphometrically in several short-term clinical studies, but data from long-term clinical studies are difficult to achieve, as are data on the influence on bone strength.

The aim of this study was to develop a computer simulation model that could assist in predicting the long-term effects of changes in the remodeling process on bone mass, trabecular thickness, and perforations. The paper presents such a stochastic model of the remodeling process in human vertebral trabecular bone. The computer model is based on histomorphometric and structural data from human studies. It is presented in terms of flow charts, and simulations performed with the model are discussed in relation to measurements on human vertebral bone samples.

The results show that a menopause-related doubling of the activation frequency causes a transient, mainly reversible bone loss. If the menopause is accompanied by an increase in both activation frequency and resorption depth, then the resulting bone loss will be more pronounced and with a larger part being irreversible bone loss (perforations). The two antiresorptive agents Etidronate and estrogen both cause a slight increase in bone mass (reducing remodeling space), and Etidronate also seems capable of preventing perforations. During fluoride therapy, an initial increase in remodeling space followed by a reduction is seen. Very few perforations are found to take place during fluoride therapy.

The present model has been validated by assessing the effects of the menopause and treatment with antiresorptive or anabolic agents. It was found that the results mirrored very closely the results (bone mass measurements) from short-term clinical studies. It is therefore concluded that the model provides a tool for evaluating existing and new therapeutic regimens.