Molecular mechanisms for bone resorption by gingipains: Degradation of osteoprotegerin by lysine-specific gingipain is a key factor for enhanced osteoclastogenesis

BackgroundPeriodontitis is a chronic inflammatory disease accompanied by alveolar bone loss. Porphyromonas gingivalis, which plays a key role in the etiology of periodontitis, produces cysteine proteases called gingipains to promote proteolysis. Gingipains are classified into two groups based on their cleavage site specificity, specifically arginine-specific gingipains (Rgps) and lysine-specific gingipains (Kgps).HighlightWe found that osteoclast differentiation induced by active vitamin D₃, Toll-like receptor ligands including lipopolysaccharide, and inflammatory cytokines such as tumor necrosis factor-α and interleukin-1β was enhanced by a secreted Kgp in co-cultures of mouse osteoblasts and bone marrow cells, whereas RgpB had no effect on osteoclast differentiation under the same experimental conditions. The effect of Kgp on osteoclast differentiation was completely blocked by an inhibitor of Kgp. Further, osteoprotegerin (OPG), a protein that regulates osteoclast differentiation, was degraded by Kgp. Kgp-mediated osteoclast differentiation was not observed in co-cultures of OPG-deficient osteoblasts and bone marrow cells.ConclusionOur data suggests that degradation of OPG by Kgp is a crucial event in the progression of osteolysis in periodontitis.     

Piezo1介导的机械应力刺激在抗骨质疏松中的作用

背景：机械敏感通道蛋白Piezo1是机械应力刺激的重要靶蛋白,能将物理的机械力转化成生物电信号,从而调控骨形成与骨吸收,在抗骨质疏松中发挥着重要作用。目的：总结机械应力刺激在抗骨质疏松中的作用机制、Piezo1分子生物学研究进程及Piezo1在骨质疏松中的研究进展。方法：使用计算机在中国知网、万方、维普、Pub Med及Web of Science数据库进行文献检索,中文检索词为“骨质疏松、Piezo1、机械应力、骨”,英文检索词为“osteoporosis,Piezo1,mechanical,osteoblast,osteoclast,chondrocyte,bone”,根据纳排标准对文献进行筛选,最终纳入65篇文献进行综述。结果与结论：(1)机械敏感通道蛋白Piezo1的蛋白结构在冷冻电镜技术突破中不断得到新的解析,目前研究表明Piezo1蛋白基于三叶螺旋桨状三维构造主体,在静默和应激状态下可表现出不同的结构变化;(2)Piezo1介导的机械应力刺激能通过调控成骨细胞、软骨细胞、内皮细胞、肠道细胞的功能影响骨形成,同时调控破骨细胞的功能影响骨吸收,进而在抗骨质疏松中发挥重要作用;(...     

Post-natal bone physiology

Post-natal bone development is characterized by substantial longitudinal bone growth and changes in skeletal size and shape. Bone is in a dynamic process of continuous remodeling which helps to regulate calcium homeostasis, repair micro-damage to bones from everyday stress, and to shape the skeleton during growth. Bone growth is regulated by systemic hormones and locally generated factors. Understanding their mechanisms of action enables us to obtain a better appreciation of the cellular and molecular basis of bone remodeling and could therefore be valuable in approaches to new therapies. This article will review molecular and cellular control of skeletal growth in the post-natal period, the physiology of each bone cell with their systemic and local regulators, as well as the physiology of bone remodeling.     

巨噬细胞集落刺激因子对破骨细胞活性的影响

巨噬细胞集落刺激因子(M-CSF)是目前临床上应用最广泛的细胞因子之一,因其具有独特和良好的升白细胞及干细胞动员作用,得到临床医师的肯定。M-CSF可诱导人破骨细胞形成,刺激其分化、存活,参与成熟破骨细胞对骨的吸收作用;而且可以抑制破骨细胞凋亡,因而可用于治疗骨骼石化症。虽然有关M-CSF对破骨细胞的生长、分化和凋亡的影响已有较广泛的研究,但对其确切的细胞生物学机制并不很清楚,本文综述了近年来该方面的研究进展。     

抗骨质疏松药物作用机制和研发靶点

成骨细胞和破骨细胞功能失衡以及耦联机制的破坏是骨质疏松和代谢性骨病的主要发病机制.抗骨质疏松药物的研发大多通过直接影响此两群细胞的信号和代谢通路而改变其活性.目前成骨细胞信号的研发靶点主要集中在甲状旁腺激素(PTH)通路和Wnt信号通路等,而破骨细胞则主要集中在核因子κB受体激活因子及其配体(RANK/RANKL)通路和整合素αvβ3通路等.     

The osteoclast: a potential therapeutic target of bone and joint destruction in rheumatoid arthritis

There is accumulating evidence that osteoclasts, the primary cells responsible for bone resorption, are involved in bone and joint destruction in rheumatoid arthritis (RA). Recent progress in bone cell biology has revealed the molecular mechanism of osteoclast differentiation and bone resorption by mature osteoclasts. We here highlight the potential role of RANKL–RANK pathways in bone destruction in RA. We also describe our recent trials on gene therapy of arthritic joint disease targeting osteoclasts by regulating Src kinase activity in the cells.     

雷公藤甲素通过抑制破骨细胞生成预防骨丢失的研究

目的 探讨雷公藤甲素抗骨质疏松的作用及机制。方法 建立大鼠老年性骨质疏松模型。40只22月龄雄性SD大鼠随机分为雷公藤甲素（每天15μg/kg腹腔注射）治疗组和生理盐水对照组（每天15μg/kg腹腔注射）,连续8周。采用显微CT分析胫骨近端骨松质的骨密度(BMD)和骨显微结构。WB检测成骨相关蛋白表达水平。TRACP-5b染色法测定破骨细胞数,同时检测骨吸收标志物表达水平。结果 显微CT结果显示,雷公藤甲素治疗组大鼠骨密度、骨体积/总体积比值(Bv/Tv)、骨小梁厚度(Tb.Th)、骨小梁数目(Tb.N)、骨小梁间距(Tb.Sp)均显著高于对照组（P<0.05）。两组的成骨相关蛋白表达水平无明显差异,TRACP-5b染色显示雷公藤甲素减少了体内破骨细胞的数量（P<0.05）,同时血液骨吸收标志物水平也明显降低（P<0.05）。结论 雷公藤甲素通过抑制破骨细胞生成进而对老年性骨质疏松有保护作用。雷公藤甲素可能是治疗老年性骨质疏松症的一种可行方案。     

RANKL-independent modulation of osteoclastogenesis

Osteoclasts are functional cells required for bone resorption. They are derived from hematopoietic precursors and undergo a series of differentiation and fusion steps in response to various humoral factors. Depending on the importance in osteoclastogenesis, the pathways for the differentiation of hematopoietic precursors to mature osteoclasts can be divided into two categories: canonical and the non-canonical. Receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast formation is considered as an important canonical pathway. Non-canonical pathways of osteoclastogenesis mainly involve several humoral factors that can substitute for RANKL to induce osteoclast formation. Among these factors, tumor necrosis factor (TNF)-α, interleukin (IL)-1, “homologous to lymphotoxins, exhibiting inducible expression, and competing with herpes simplex virus glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes” (LIGHT), a proliferation-inducing ligand (APRIL), and B cell-activating factor (BAFF) belong to the TNF superfamily. Other RANKL substitutes are primarily cytokines and growth factors including transforming growth factor β (TGFβ), IL-6, IL-11, nerve growth factor (NGF), insulin-like growth factor (IGF)-I, and IGF-II. In this review, we summarize the involvement of these factors in inducing osteoclastogenesis in vitro. Although these factors weakly induce osteoclast formation, they may play a major role in pathological bone resorption.     

帕米膦酸钠对大鼠正畸牙移动过程中破牙骨质细胞及破骨细胞分化因子表达的影响

目的:研究帕米膦酸钠对大鼠正畸牙移动过程中牙周组织压力侧破牙骨质细胞及破骨细胞分化因子(ODF)表达的影响.方法:选择24只6周龄SPF级健康雌性Wistar大鼠,建立正畸牙移动动物模型,每只大鼠上颌分实验侧和对照侧,于安装矫治器前3d,于实验侧大鼠第一磨牙近中腭侧黏骨膜下注射帕米膦酸钠50 μL,对照侧注射0.9％生理盐水50 μL,每3d注射1次.于正畸加力3、7、14 d时分批处死8只大鼠,制作牙周组织切片,观察破牙骨质细胞数量,免疫组化观察ODF的表达情况.采用PASW Statistics 18软件包对实验数据进行统计学处理.结果:实验侧在3、7、14d时,第一磨牙压力侧破牙骨质细胞的数目均少于对照侧,其中,7、14d时两侧差异显著(P＜0.05);实验侧在3、7、14d时,第一磨牙压力侧ODF阳性表达均低于对照侧,其中,7、14 d时两侧差异显著(P＜0.05).结论:局部注射二膦酸盐帕米膦酸钠能够减少大鼠正畸牙移动过程中牙周组织压力侧破牙骨质细胞的数量及ODF的阳性表达.     

促红细胞生成素对破骨细胞调控机理的研究

目的研究小鼠单核巨噬细胞在体外向破骨细胞分化的过程中,促红细胞生成素（erythropoietin,EPO）与破骨细胞表面受体Epor结合发挥作用的机理。方法 EPO作用于Epor受体沉默的经诱导的小鼠单核巨噬细胞,观察TRAP阳性多核细胞数目变化。Real-time PCR检测RAW264.7向破骨细胞分化过程中相关基因Epor、Nfatc1、Mmp9、EphrinB2基因的表达。结果与对照组比较,4天后,Epor沉默组的Nfatc1、EphrinB2 mRNA的表达明显升高（P〈0.01）,Ctsk Mmp9 mRNA的表达明显降低（P〈0.01）。结论 EPO通过与破骨细胞表面受体Epor结合,引发破骨细胞内相关基因表达改变,进而影响破骨细胞的分化和活化。