骨细胞的力学感受器

骨细胞是骨骼中最丰富和寿命最长的细胞,是骨重建的调节器。骨细胞在内分泌调节和钙磷酸盐代谢中发挥重要作用,也是力学刺激的主要响应者,感知力学刺激以直接或间接的方式对刺激做出反应。骨细胞中的力学转导是一个复杂而精细的调节过程,涉及细胞与其周围环境、相邻细胞以及细胞内部不同功能的力学感受器之间的相互作用。目前已知的骨细胞主要力学感受器包括初级纤毛、Piezo离子通道、整合素、细胞外基质以及基于连接蛋白的细胞间连接。这些力学感受器在骨细胞中发挥着至关重要的作用,它们能够感知并转导力学信号,进而调节骨稳态。本文对5种力学感受器进行系统的介绍,以期为理解骨细胞如何响应力学刺激和维持骨组织稳态提供新的视角和认识。     

骨细胞 Cx43 在膝关节响应力学过载中的作用

目的 探究骨细胞连接蛋白43（connexin43,Cx43）通道在力学过载对小鼠膝关节影响中的作用。方法 对15周龄骨细胞特异Cx43转基因小鼠（R76W：间隙连接功能抑制而半通道功能促进;Δ130-136：间隙连接和半通道都被抑制）及同窝野生型小鼠左膝关节施加单次应变（ε=1.764 62）,右膝关节作为对照。1周后分析小鼠步态,评价小鼠膝关节骨与软骨情况。抑制MLO-Y4骨细胞Cx43通道功能后进行循环拉伸应变,检测相关因子表达。收集条件培养基培养ATDC5软骨细胞,检测相关基因表达和成骨分化能力。结果步态分析显示,Cx43通道抑制没有明显影响小鼠步态。但转基因小鼠关节股骨端OARSI评分显著增加,骨小梁面积占比更小。抑制MLO-Y4细胞Cx43通道降低了ADAMTS5和II型胶原表达,增强其成骨分化的能力。结论 骨细胞Cx43通道能够响应力学过载,影响软骨细胞关键基因表达,并参与其成骨分化过程的调控,影响软骨对力学过载的响应。研究结果为骨关节炎的防治提供新思路。     

力学载荷对破骨细胞凋亡的影响及其调节机制

破骨细胞是参与骨代谢的基本功能细胞之一.破骨细胞在骨重建过程中主要承担旧骨组织的破坏和吸收,因此,破骨细胞凋亡的微小变化都可能会改变骨重建的进程.调节破骨细胞凋亡的因素有很多,如雌激素、二磷酸盐等生物化学因素,但力学载荷对于破骨细胞生物学活性影响的研究相对较少.综述了力学载荷对破骨细胞生物学活性的影响以及细胞凋亡与破骨细胞凋亡的调节.     

以IGF-1、NOS、FGF23和硬骨素为靶基因的骨细胞力学响应微小RNA的筛选

目的 筛选骨细胞分泌因子相关力学响应微小RNA(microRNA, miRNA)。方法 分别向体外培养骨细胞和成骨细胞施加周期性张应变（ε=2.5,f=0.5 Hz）,采用miRNA芯片筛选出仅在骨细胞中差异表达的miRNA。通过生物信息学技术,从这些miRNA中进一步筛选出靶基因为胰岛素样生长因子1（insulin-like growth factor-1）、NO合成酶（nitric oxide synthesase, NOS）、成纤维细胞生长因子23(fibroblast growth factor 23, FGF23)和硬骨素(sclerostin, SOST)等分泌因子的miRNA,与小鼠跑台锻炼后芯片检测出的小鼠股骨组织差异表达miRNA进行比较,然后随机选4个miRNA进行定量PCR验证。结果 仅在体外经力学刺激的骨细胞中差异表达的77个miRNA中,筛选出22个靶基因为4种分泌因子（IGF-1、NOS、FGF23、SOST）的miRNA,并进一步筛选出11个在跑台锻炼后的小鼠骨组织中以同样趋势差异表达的miRNA,其中随机选出的miR-361-3p、miR-3082-5p、miR-6348和miR-706,也在骨细胞和骨组织中以同样趋势同样差异表达。结论 诸如miR-361-3p、miR-3082-5p、miR-6348和miR-706仅在骨细胞中差异表达的力学响应miRNA,很可能通过调节分泌因子影响成骨分化或骨代谢。     

成骨细胞和骨细胞的力学信号转导

背景:骨骼具有功能适应性的特点,骨骼细胞是力学信号敏感细胞,但细胞的力学信号转导功能是如何实现的,对骨骼如何调控仍不明确。 目的：了解成骨细胞和骨细胞的力学信号转导途径,为利用力学信号改善骨骼功能提供理论依据。 方法：应用计算机检索PubMed数据库2000-01/2011-03相关文献。英文检索词为“osteoblast,osteocyte,bone cells,mechanical stress”, 根据纳入标准共69篇文章进行综述,以此对骨骼细胞力学信号转导相关内容进行总结。 结果与结论：骨骼具有功能适应性的特点,骨骼细胞是力学信号敏感细胞,但细胞的力学信号转导功能是如何实现的,对骨骼具有怎样的调控仍不明确。研究表明,由于骨骼的结构特点和细胞位置,成骨细胞和骨细胞是最重要的力学敏感性细胞。力学信号在骨骼内的转导过程分为4个阶段：①力学偶联。②生化偶联。③信号的传递。④效应性细胞的反应。通过这4个阶段的作用,作用在骨骼上的应力信号转导为生物化学信号,并影响细胞的功能,最终导致骨骼组织出现相应的结构变化以适应应力环境的需要。对于力学信号在骨髓间充质干细胞中的调控机制还有待继续深入探索。     

骨骼肌通过力学刺激对骨重建的影响

骨骼与骨骼肌作为运动系统最重要的组织,两者之间存在密切的联系。骨肌单元的概念提出已久,运动产生的力学负荷将两者紧密地联系在一起。骨骼为骨骼肌施力提供力学支撑,而骨骼肌收缩带动机体的运动。在机体运动过程中,骨骼肌充当力学负荷与骨骼之间的中间媒介,并通过内分泌因子以及力学信号调节骨骼的代谢活动,与机体内持续不断的骨重建密切相关,并维持骨骼良好的结构和功能。主要综述近年来骨骼肌通过对骨骼施加力学刺激影响骨重建作用的研究进展,为预防和治疗骨代谢疾病提供新的思路。     

载荷作用下骨细胞分泌因子对成骨细胞和破骨细胞的调节

骨细胞是骨组织主要的力学感受及转导细胞,它们通过众多突触结构相互连接,形成庞大的骨稳态细胞调控网络,联系着成骨细胞、破骨细胞等骨基质表面细胞。骨细胞通过旁分泌途径影响成骨细胞骨形成和破骨细胞骨吸收来调节骨代谢,维持骨更新。针对骨细胞在受到力学刺激后分泌或释放的一些信号分子或蛋白因子对成骨细胞和破骨细胞生长分化的影响,本文综述近年来关于受力学刺激的骨细胞如何与成骨/破骨细胞进行通讯,为骨细胞生物力学研究提供新思路。     

破骨细胞细胞骨架的研究进展

破骨细胞是由造血细胞源的单核前体细胞相互融合而成的一种特殊巨噬多核细胞，在骨吸收过程的不同阶段破骨细胞的表型出现很大的改变，同时，破骨细胞内的细胞内架进行了广泛的重组。本文就近年来有关破骨细胞在吸收周期中细胞骨架的变化，作用及其调节的研究进展和前景作了综述。     

阿仑膦酸钠对兔破骨细胞功能的影响

用骨陷窝形成分析法观察阿仑膦酸钠对体外培养破骨细胞功能的影响，探讨可能的作用机制。在建立兔破骨细胞培养方法的基础上，用不同浓度的阿仑膦酸钠分别与骨片或成骨细胞提前作用，然后再将骨片或成骨细胞分别与破骨细胞共同培养。结果发现当阿仑膦酸钠（10^-11,10^-9,10^-7mol/L)与骨片预处理后，破骨细胞在骨片上形成的骨吸收陷窝数目减少，其抑制率分别为19．5％（P＜0．05）、49．0％（P＜0．01）和74．5％（P＜0．01）。用阿仑膦酸钠（10^-9,10^-7,10^-5mol/L)预处理成骨细胞后，仅在高浓度（10^-5mol/L）时可见破骨细胞骨吸收陷窝的数目明显减少，其抑制率为62．8％（P＜0．01）。结果表明阿仑膦酸钠能直接或通过成骨细胞间接抑制破骨细胞的骨吸收活性。     

破骨细胞细胞骨架的研究进展

破骨细胞是由造血细胞源的单核前体细胞相互融合而成的一种特殊巨噬多核细胞 ,在骨吸收过程的不同阶段破骨细胞的表型出现很大的改变 ,同时 ,破骨细胞内的细胞内架进行了广泛的重组。本文就近年来有关破骨细胞在吸收周期中细胞骨架的变化、作用及其调节的研究进展和前景作了综述     

力学刺激通过microRNA调控骨重建的研究进展

骨骼结构完整性和骨量的维持需要一定的力学刺激。研究表明,力学刺激可通过调控多种调节因子(例如激素、转录因子和信号分子等)参与骨重建过程。力学刺激可以通过调控微小RNA(microRNA,miRNA)表达在骨重建过程中起着至关重要的作用。然而,受力学刺激调控的miRNA在骨重建过程中的作用和机制尚不完全清楚。本文综述受力学刺激调控的miRNA在骨重建过程中的作用及其机制,并强调其在治疗骨质疏松中的潜在应用。     

Stimulation of Cell Component of the Immune Response Activates Exploratory Behavior in Senescence Accelerated OXYS Rats

Suppression of the cell component of the immune system and open-field behavior developing in OXYS rats by the age of 3 months are regarded as manifestations of accelerated aging. Stimulation of cell-mediated immune response with BCG vaccine caused a dose-dependent increase of orientation and exploratory activity of OXYS rats in the open field test to virtually the same level as in Wistar rats. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 140, No. 9, pp. 332–334, September, 2005     

Notch信号通路在骨重建中的作用

Notch信号通路在胚胎发育、神经系统、血管系统、内分泌系统及肿瘤等领域具有广泛的影响。近年来的研究表明,Notch对于骨组织代谢尤其是骨重建有着重要的调控作用,而骨重建的调节紊乱和骨质疏松、骨关节炎等疾病的进展密切相关。Notch信号通路可以通过调控骨组织不同细胞的功能从而影响骨重建过程,但其在不同细胞中具体的参与方式仍然未知。综述近年来Notch信号通路在骨重建中的作用研究进展。     

Attachment of Osteocyte Cell Processes to the Bone Matrix

In order for osteocytes to perceive mechanical information and regulate bone remodeling accordingly they must be anchored to their extracellular matrix (ECM). To date the nature of this attachment is not understood. Osteocytes are embedded in mineralized bone matrix, but maintain a pericellular space (50–80 nm) to facilitate fluid flow and transport of metabolites. This provides a spatial limit for their attachment to bone matrix. Integrins are cell adhesion proteins that may play a role in osteocyte attachment. However, integrin attachments require proximity between the ECM, cell membrane, and cytoskeleton, which conflicts with the osteocytes requirement for a pericellular fluid space. In this study, we hypothesize that the challenge for osteocytes to attach to surrounding bone matrix, while also maintaining fluid‐filled pericellular space, requires different “engineering” solutions than in other tissues that are not similarly constrained. Using novel rapid fixation techniques, to improve cell membrane and matrix protein preservation, and transmission electron microscopy, the attachment of osteocyte processes to their canalicular boundaries are quantified. We report that the canalicular wall is wave‐like with periodic conical protrusions extending into the pericellular space. By immunohistochemistry we identify that the integrin αvβ3 may play a role in attachment at these complexes; a punctate pattern of staining of β3 along the canalicular wall was consistent with observations of periodic protrusions extending into the pericellular space. We propose that during osteocyte attachment the pericellular space is periodically interrupted by underlying collagen fibrils that attach directly to the cell process membrane via integrin‐attachments. Anat Rec, 292:355–363, 2009. © 2009 Wiley‐Liss, Inc.     

Analysis of the Effect of Osteon Diameter on the Potential Relationship of Osteocyte Lacuna Density and Osteon Wall Thickness

An important hypothesis is that the degree of infilling of secondary osteons (Haversian systems) is controlled by the inhibitory effect of osteocytes on osteoblasts, which might be mediated by sclerostin (a glycoprotein produced by osteocytes). Consequently, this inhibition could be proportional to cell number: relatively greater repression is exerted by progressively greater osteocyte density (increased osteocytes correlate with thinner osteon walls). This hypothesis has been examined, but only weakly supported, in sheep ulnae. We looked for this inverse relationship between osteon wall thickness (On.W.Th) and osteocyte lacuna density (Ot.Lc.N/B.Ar) in small and large osteons in human ribs, calcanei of sheep, deer, elk, and horses, and radii and third metacarpals of horses. Analyses involved: (1) all osteons, (2) smaller osteons, either ≤150 μm diameter or less than or equal to the mean diameter, and (3) larger osteons (>mean diameter). Significant, but weak, correlations between Ot.Lc.N/B.Ar and On.W.Th/On.Dm (On.Dm = osteon diameter) were found when considering all osteons in limb bones (r values ?0.16 to ?0.40, P < 0.01; resembling previous results in sheep ulnae: r = ?0.39, P < 0.0001). In larger osteons, these relationships were either not significant (five/seven bone types) or very weak (two/seven bone types). In ribs, a negative relationship was only found in smaller osteons (r = ?0.228, P < 0.01); this inverse relationship in smaller osteons did not occur in elk calcanei. These results do not provide clear or consistent support for the hypothesized inverse relationship. However, correlation analyses may fail to detect osteocyte‐based repression of infilling if the signal is spatially nonuniform (e.g., increased near the central canal). Anat Rec,, 2011. © 2011 Wiley‐Liss, Inc.     

A Morphological Analysis on the Osteocytic Lacunar Canalicular System in Bone Surrounding Dental Implants

Osseointegration is the most preferable interface of dental implants and newly formed bone. However, the cavity preparation for dental implants often gives rise to empty lacunae or pyknotic osteocytes in bone surrounding the dental implant. This study aimed to examine the chronological alternation of osteocytes in the bone surrounding the titanium implants using a rat model. The distribution of the osteocytic lacunar canalicular system (OLCS) in bone around the titanium implants was examined by silver impregnation according to Bodian's staining. We also performed double staining for alkaline phosphatase (ALP) and tartrate‐resistant acid phosphatase (TRAP), as well as immunohistochemistry for fibroblast growth factor (FGF) 23—a regulator for the serum concentration of phosphorus—and sclerostin, which has been shown to inhibit osteoblastic activities. Newly formed bone and the injured bone at the early stage exhibited an irregularly distributed OLCS and a few osteocytes positive for sclerostin or FGF23, therefore indicating immature bone. Osteocytes in the surrounding bone from Day 20 to Month 2 came to reveal an intense immunoreactivity for sclerostin. Later on, the physiological bone remodeling gradually replaced such immature bone into a compact profile bearing a regularly arranged OLCS. As the bone was remodeled, FGF23 immunoreactivity became more intense, but sclerostin became less so in the well‐arranged OLCS. In summary, it seems likely that OLCS in the bone surrounding the dental implants is damaged by cavity formation, but later gradually recovers as bone remodeling takes place, ultimately inducing mature bone. Anat Rec,, 2011. © 2011 Wiley‐Liss, Inc.     

妇女绝经、老龄对骨质疏松的影响

骨质疏松严重危害妇女绝经后的生活质量.本文介绍了骨质疏松的生理原因和带有力学调控系统的各向异性骨再造模型,应用该模型用有限元方法对妇女绝经骨质疏松进行数值模拟.结果表明:单纯绝经因素骨量降低7%～12%,绝经后载荷下降20%,两种因素共同引起的结果,使骨量下降25%～29%,如载荷下降40%,骨量丢失35%左右.可见,力学因素是导致妇女绝经后骨质疏松的主要因素,生物学因素则加速了骨质疏松的过程.此结果证明了力学因素对于骨量的维持起着重要作用,为骨质疏松的研究开辟了一个新的思路.