白细胞介素4与骨重建

白细胞介素４与骨重建德州市人民医院内科（２５３０１４）周尊海，李荣华综述近年来，细胞因子在调节骨代谢方面的作用受到普遍关注，并已证实许多细胞因子直接或间接参与调节骨细胞的功能与活性，从而影响骨重建。本文主要简述ＩＬ－４对骨重建细胞一成骨细胞的骨形成作...     

Notch信号通路与骨发生和骨重建

Notch信号通路对调节胚胎细胞和成体细胞增生、分化、凋亡以及前体细胞的自我更新具有重要意义。它可通过协调胚胎期生长板内软骨细胞分化和生长,控制骨组织正常发生。骨重建是对病损骨组织的再生和修复,主要由成骨细胞和破骨细胞参与,Notch信号除可对上述2种细胞增生、分化、成熟等进行调控外,也可介导依赖于成骨细胞的破骨细胞生成。本文试以Notch信号对软骨细胞、成骨细胞、破骨细胞等细胞学行为改变为主线,探讨Notch信号对上述2种骨生物学行为调节的作用机制。     

应力负荷与骨骼结构及骨重建的关系

应力负荷是骨质量和骨骼几何形状的主要调节因子.骨细胞信号网络通过感知骨骼力学负荷而发挥作用,是应力负荷的主要传感器.骨细胞死亡后发生骨重建,骨骼力学负荷减小或丧失.骨折后所致长期卧床、局部制动导致骨细胞凋亡和骨吸收,引起严重的骨质疏松.通过分析骨骼适应应力负荷的机制,骨细胞感受机械刺激和骨骼的力学负荷,力学负荷对骨骼的作用和应力负荷与骨重塑过程的分子调控等,可以探讨应力负荷与骨骼结构及与骨重建的关系.     

密质骨弥散性微损伤非骨重建自修复

弥散性微损伤是骨疲劳引发的主要骨微损伤之一。骨损伤修复普遍认为完全通过骨重建过程完成。研究发现与线性裂痕不同,弥散性微损伤的骨细胞未凋亡,损伤区在"无骨重建过程"下进行了直接修复。基于此新发现,本文对弥散性基质微损伤的特殊自修复相关机制研究进行综述,旨在为骨微损伤修复研究提供一个新视角,并为临床治疗骨组织疾病提供新思路。     

转化生长因子在骨重建中的作用

转化生长因子是骨中含量最多的一种生长因子。本文从转化生长因子对体外成骨细胞、破骨细胞的影响，对体内骨形成的影响，在临床上的应用前景以及其对骨重建的调节机制等方面作一简要综述。     

胰岛素样生长因子－1与骨重建

本文介绍了胰岛素样生长因子－１（ＩＧＦ－１）与骨重建的研究进展，包括ＩＧＦ－１对成骨细胞和破骨细胞的作用，以及对１ＧＦ－１用于治疗骨质疏松的展望。     

骨代谢标志物和骨矿密度在骨质疏松症中的应用

骨骼作为机体的一种器官,同样处于不断的新陈代谢中,正常骨组织一直周而复始地进行骨重建,骨重建包括骨形成和骨吸收这两个方面,骨形成和骨吸收在正常情况下处于一定的动态平衡。当骨吸收大于骨形成,就会发生骨量减少,甚至骨质疏松。目前国际上确诊骨质疏松症的金标准是采用双能X线法测定骨密度。但这种骨骼形态学上的改变往往需要比较长的时间才能被察觉,虽然骨代谢标志物并不能作为诊断骨质疏松症的标准,不过可以较快速、灵敏地显示骨吸收和重建状态,能够动态的反映体内骨重建的状况,对监测药物疗效、评价骨质量、预防骨质疏松、鉴别诊断代谢性骨病等有着重要的临床意义。     

嵌入固定法重建前交叉韧带:肌腱-骨和肌腱结的生物力学和组织学研究

目的 探讨肌腱-骨和肌腱结两种移植物重建前交叉韧带（ACL）的生物力学效果和组织学转归情况。方法 生物力学部分采用猪膝关节45个模拟交叉韧带重建。实验分为：骨-髌腱-骨（B-PT—B）界面螺钉固定法（n=11）、股骨端单纯肌腱结（n=13）和肌腱-骨（n=11）嵌压固定法；猪正常膝关节（n=8）ACL作为实验对照组。观察最大载荷拔出、刚度和最大位移等指标，数据进行统计学处理。组织学部分用10只山羊膝关节为实验模型，股骨隧道呈倒置瓶颈状，分别以髌腱-胫骨结节骨块或趾长伸肌腱结为移植物，在股骨隧道内嵌压固定重建前交叉韧带。术后4、8、12、16周取材，分别进行放射学、大体形态和组织切片检查，观察隧道宽度变化及移植物的组织学转归。结果 最大载荷：肌腱结和肌腱-骨嵌压固定法〉B-PT—B界面螺钉固定。前者可以满足正常生理强度需求。两组移植物术后各时间点放射检查未见隧道扩大；HE染色检查显示12周后有明显的腱-骨连接形成。结论 股骨端肌腱结和肌腱-骨两种移植物采用嵌压固定法重建ACL，其最大载荷强度〉B-PT—B界面螺钉固定法，能满足日常生理活动需求，有利于移植物的愈合。     

骨保护素对骨代谢的调控作用

骨保护素（OPG）是近年来骨代谢研究领域新发现的一种可溶性肿瘤坏死因子（TNF）受体。近年来。OPG已被证实可调控破骨细胞（OC）和骨吸收，在骨吸收与重建中起关键作用，在代谢性骨病的发病和治疗中起重要作用。现结合文献对OPG的结构特征及其对骨代谢、代谢性骨病的影响综述如下。     

骨量的中枢调控,骨重建与能量代谢的首要联系

人体内是否存在某个惰性或几乎静止不变的器官?答案当然是否定的.然而,如果说人体内是否存在某个相对不活跃的器官,答案则是完全肯定的.以骨骼为例,早期的大多数人(包括临床医师和科学家)认为骨骼只是钙化管状结构的集合体,其结构与功能几乎不发生明显变化.直到20世纪40年代我们才发现,骨重建(Bone remodeling)--脊椎动物骨组织自我更新--的生理功能受到性腺、甲状旁腺等远距离内分泌腺的调控.从概念上来说,这两种内分泌调控因子的存在使其他内分泌因子参与调控骨量的假说成为可能.     

Clinical application of metabolic bone markers for fracture - effects of fracture on metabolic bone markers -

The process of fracture healing can be divided into three distinct stages - inflammatory, reparative and remodeling stages. The changes of bone formation and bone resorption in the process of fracture healing are expected to be more dynamic than those changes which occur in the remodeling cycle alone because of aging. Bone formation and bone resorption markers increased 1 or 2 weeks after fracture. Bone resorption markers returned to the baseline level at 24 weeks after fracture, while values of bone formation marker were still higher compared to the baseline level at 24 weeks after fracture. It is suggested that bone metabolism is still activated at 24 weeks after fracture. In the acute phase after fracture, many factors such as bed rest, skin incision, intramedullay reaming during operation, could modify the values of bone resorption and bone formation markers. Therefore, clinical application of metabolic bone markers for fracture might be useful in the remodeling stage after fracture.     

Bone re/modeling is more dynamic in the endothelial nitric oxide synthase(-/-) mouse

Nitric oxide is a ubiquitous estrogen-regulated signaling molecule that has been implicated in the regulation of bone maturation and remodeling. To better understand the role that bone-cell-secreted nitric oxide plays in ovariectomy-induced modifications of bone turnover, we examined the expression of endothelial NO synthase (eNOS) in bone cells and bone progenitor cells at regular intervals up to 10 wk after acute estrogen deprivation. Ovariectomy led to an anticipated initial decline in bone cell eNOS production, but surprisingly, 17 d after ovariectomy, eNOS expression by bone and marrow stromal cells dramatically rebounded and was maintained at high levels for at least 10 wk after surgery. We examined the long-term consequences of eNOS in the process of ovariectomy-induced bone loss by prospectively analyzing bone mineral density in wild-type and eNOS(-/-) mice for 10 wk after ovariectomy. Ovariectomized eNOS(-/-) mice were observed to undergo an exaggerated state of estrogen-deficiency-induced bone remodeling compared with wild-type controls, suggesting that eNOS may act to mitigate this process. Furthermore, we found that whereas bone formation in estrogen-replete wild-type mice slowed between 14 and 20 wk of age, eNOS knockout mice continued to accrue basal bone mass at a high rate and showed no sign of entering a remodeling stage. Our data suggest that eNOS may play an important role in limiting ovariectomy-induced bone remodeling as well as regulating the transition from basal modeling to remodeling.     

Bone quality in fracture callus

We reviewed the effect of agent for osteoporosis on fracture healing. Bisphosphonates increased the callus volume, while delaying remodeling of the callus woven bone into lamellar bone, which is structurally and mechanically superior to woven bone. Selective estrogrn receptor modulator mildly suppressed callus remodeling, which had no effect on fracture repair and intrinsic material properties. Intermittent treatment of parathyroid hormone accelerated the healing process as evidenced by earlier replacement of woven bone to lamellar bone, increased new cortical shell formation, and increased the ultimate load.     

Mechanisms of action of antiresorptive therapies of postmenopausal osteoporosis

In the treatment of osteoporosis, the aim of the antiresorptive therapy is to restore bone density by decreasing bone remodeling. The process of bone remodeling plays a role in plasma calcium homeostasis and serves to modify bone architecture in order to meet changing mechanical needs, to maintain osteocyte viability, and to repair microdamage in bone matrix. Estrogen deficiency results in a number of detrimental effects on bone, including suppression of osteocyte survival as well as impairment of osteoblast response to mechanical stimuli and repair of ageing bone. In this review, effects of available antiresorptive therapies on endocrine regulations of bone metabolism in postmenopausal osteoporosis are compared. The aim of antiresorptive treatment is to ensure adequate bone remodeling, reparation of microdamage of bone, and increased bone strength. Ideally, this effect should be maintained long-term. Several agents are approved for the treatment of osteoporosis. Calcitonin transiently inhibits osteoclast activity without decreasing osteoblast collagen synthesis. Aminobisphosphonates decrease bone remodeling by decreasing osteoclast activity and by inducing osteoclast apoptosis. This allows more time for secondary mineralization to proceed to completion in the existing bone tissue mass, so increasing the mechanical resistance of bone to loading. Estrogens and raloxifene (a selective estrogen receptor modulator that acts as an estrogen agonist in bone) suppress bone remodeling to the premenopausal range, maintaining the function of osteoblasts and osteocytes. In the placebo-controlled osteoporosis treatment trials, all the above treatments reduced the risk of fractures. Raloxifene therapy was also associated with a favorable or neutral effect in the cardiovascular system, and a reduced incidence of breast cancer. Selection of appropriate drug for treatment of postmenopausal osteoporosis should take into account the long-term effect of the antiresorptive agent on bone. Moreover, the effects on other tissues ++should also be considered, and this encompasses both safety concerns, as well as the potentially beneficial effects on other tissues. Further investigation is needed to evaluate the different modes of action of these agents, and their long-term effects on bone and other tissues.     

Role of RANKL-RANK/osteoprotegerin molecular complex in bone remodeling and its immunopathologic implications

Bone remodeling is a cyclic and continuous physiological process, which ensures the conservation and renewal of the bone matrix. Osteosynthesis of the bone matrix is achieved by osteoblasts and coordinated within this complex machinery of bone remodeling with resorption of extracellular bone matrix performed by osteoclasts. The mismatch between the activities of osteoblasts and osteoclasts has immunopathologic implications associated with either a decrease or increase of bone mass mineral density. The balance of the trimolecular control factor complex composed of osteoprotegerin (OPG), RANKL (osteoprotegerin ligand) and RANK maintains physiologic bone remodeling. This trimolecular complex functions as receptors and ligands and belongs to the superfamily of tumor necrosis factor (TNF). This mini review highlights the complex interplay of the RANKL-RANK/OPG axis and their immunopathologic implications in clinical medicine.     

Cellular mechanisms of bone remodeling

Bone remodeling is a tightly regulated process securing repair of microdamage (targeted remodeling) and replacement of old bone with new bone through sequential osteoclastic resorption and osteoblastic bone formation. The rate of remodeling is regulated by a wide variety of calcitropic hormones (PTH, thyroid hormone, sex steroids etc.). In recent years we have come to appreciate that bone remodeling proceeds in a specialized vascular structure,—the Bone Remodeling Compartment (BRC). The outer lining of this compartment is made up of flattened cells, displaying all the characteristics of lining cells in bone including expression of OPG and RANKL. Reduced bone turnover leads to a decrease in the number of BRCs, while increased turnover causes an increase in the number of BRCs. The secretion of regulatory factors inside a confined space separated from the bone marrow would facilitate local regulation of the remodeling process without interference from growth factors secreted by blood cells in the marrow space. The BRC also creates an environment where cells inside the structure are exposed to denuded bone, which may enable direct cellular interactions with integrins and other matrix factors known to regulate osteoclast/osteoblast activity. However, the denuded bone surface inside the BRC also constitutes an ideal environment for the seeding of bone metastases, known to have high affinity for bone matrix. Circulating osteoclast- and osteoblast precursor cells have been demonstrated in peripheral blood. The dominant pathway regulating osteoclast recruitment is the RANKL/OPG system, while many different factors (RUNX, Osterix) are involved in osteoblast differentiation. Both pathways are modulated by calcitropic hormones.     

Bone quality, strength, and turnover

Skeletal integrity is maintained by remodeling, a sequential process of bone resorption and formation. Bone mass and quality depends on a dynamic equilibrium between resorption and formation during a remodeling process. Bone strength, or its ability to resist to fractures, is determined by both mass and quality of bone. Recent clinical studies indicate that activity of remodeling, i.e., bone turnover, is not only a predictor of future changes in bone mass but also a determinant of the future fracture risk independent of bone mass and that fracture prevention by anti-resorptives cannot be solely explained by increased bone mass but is more closely associated with improved bone quality, especially, suppression of bone turnover. This review will focus on the impact of bone turnover on bone quality and fracture risk and its clinical relevance.     

Evaluation of bone quality in terms of degree of mineralization

Quantification of degree of mineralization has recently drawn considerable attention as an evaluation method of bone quality. Degree of mineralization of bone is a main determinant factor for tissue material property of bone, and also closely associated with bone remodeling, fatigue process, and mechanical environment of bone.     

Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease

Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts. The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle. Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture. Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor kappaB ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling. The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK. Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength. RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis. Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis.     

Biomechanics

Therapeutic agents used to treat osteoporosis reduce the incidence of vertebral and nonvertebral fractures in osteoporotic women. The antiremodeling agents, such as the bisphosphonates, prevent bone loss by suppressing the remodeling rate, perhaps increasing bone volume slightly, and increasing mineralization of the tissue. The anabolic agents, of which rhPTH(1–34) is the only one approved, accomplish this in a manner that is almost completely the opposite in terms of biological process. rhPTH(1–34) causes net bone gain by stimulating both modeling and remodeling, by increasing bone volume significantly through direct bone apposition to trabecular and endocortical surfaces, and by reducing the mean degree of tissue mineralization (a natural consequence of enhanced remodeling). Each of these treatments maintains or increases bone strength and is similarly effective at preventing fractures. However, because of their different mode of action, each has different consequences for bone matrix quality (defined here by microdamage accumulation and by the properties of mineral and collagen) and the mechanical properties of the tissue. Although bone's composite nature makes it a relatively tough material—more like fiberglass than glass—the accumulation of damage will nevertheless reduce its residual mechanical properties until the damage is repaired through remodeling. Agents that suppress remodeling are associated with both microdamage accumulation and increased mineralization. The biological importance of damage and mineralization to bone's mechanical properties is still a source of debate.