骨细胞在骨重建中的功能与作用

背景：骨细胞在骨组织中形成遍布矿化骨基质的三维细胞网络,可以作为骨代谢重要的调节因子。目的：分析讨论骨细胞在骨重建过程中功能的研究进展。方法：应用计算机检索PubMed数据库、ELSEVIER数据库1990年1月至2012年4月有关骨细胞功能及骨重建的文章,检索词“osteocytes,remodeling”。同时检索万方数据库1990年1月至2012年4月相关文章,检索词“骨细胞,骨重建”。选出有代表意义的41篇进行归纳总结,排除重复或类似的同一研究。结果与结论：骨细胞对于应力的感受与反应使得骨细胞在骨重建中发挥着重要的作用,包括骨重建的启动、骨吸收抑制以及骨形成的调节。研究表明骨细胞的突触可能作为应力造成细胞变形的直接感受器。实验证明骨细胞受应力刺激后可能激活Wnt／Lrp通路作为硬化蛋白的负调节因子,而硬化蛋白本身是骨形成的负调节因子,骨细胞在重建过程中可能还承担着控制骨基质填充速度的角色。     

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。     

Bone formation in rat calvaria ceases within a limited period regardless of completion of defect repair

A bone defect that is not repaired with bone completely is designated a non-union defect or a critical-size defect. The biological mechanism that regulates the process of bone repair of the critical-size defect remains unknown. The present study was designed to investigate bone repair in a critical-size defect compared with that in a smaller or non-critical-size defect. Our original standardized rat calvarial bone defect model was used for the experiment. The rate of bone formation was examined with X-ray morphometry and the bone production of osteoblasts and osteocytes was assessed by molecular histology with in situ hybridization for type I collagen and osteocalcin. Formation of repaired bone ceased within 24 weeks in both critical- and non-critical-size defects i.e. regardless of completion of the defect repair. The results suggested that osteoblasts and osteocytes cease bone formation, and the differentiation of osteoblast progenitors declines in 24 weeks. Also, bone repair proceeds from the periosteum on both sides of the parietal bone but not from the surface of the bony edge around the original defect. The results could provide useful information for clinical research on bone repair.     

Effect of Nanoscale Topography of Titanium Implants on Bone Vessel Network,Osteocytes, and Mineral Densities

Background: Chemical and physical properties of an implant surface have a major influence on the structure of peri‐implant bone and thus may influence the clinical performance of the implant. This study aims to evaluate the bone microstructure around implants with and without added nanometer‐sized calcium phosphate particles. Methods: An implant with dual acid‐etched surface (control) and an implant with dual acid‐etched surface and CaP nanoparticles (test) were placed in the posterior maxilla of 15 patients. Bone microstructure was evaluated for osteocyte density (OD), bone vessel volume density (BVVD), and bone mineral density (BMD). Results: BVVD was 1.806 ± 0.05 for test implants and 1.533 ± 0.10 for control implants (P <0.001). BMD_low was 17.4 × 10⁴ µm² for test implants and 15.0 × 10⁴ µm² for control implants (P = 0.025). Results from the BMD_high comparison, test versus control, were not statistically significant (P >0.05). OD was 575.6 ± 63.7 mm² for test implants and 471.2 ± 61.9 mm² for control implants (P <0.001). Conclusions: After 8 weeks of healing, the bone microstructure around test implants appeared to be significantly more organized. Clinical implications of these results include shortened healing time and indication for earlier loading protocols.     

Fossilized cell structures identify an ancient origin for the teleost whole-genome duplication

Teleost fishes comprise one-half of all vertebrate species and possess a duplicated genome. This whole-genome duplication (WGD) occurred on the teleost stem lineage in an ancient common ancestor of all living teleosts and is hypothesized as a trigger of their exceptional evolutionary radiation. Genomic and phylogenetic data indicate that WGD occurred in the Mesozoic after the divergence of teleosts from their closest living relatives but before the origin of the extant teleost groups. However, these approaches cannot pinpoint WGD among the many extinct groups that populate this 50- to 100-million-y lineage, preventing tests of the evolutionary effects of WGD. We infer patterns of genome size evolution in fossil stem-group teleosts using high-resolution synchrotron X-ray tomography to measure the bone cell volumes, which correlate with genome size in living species. Our findings indicate that WGD occurred very early on the teleost stem lineage and that all extinct stem-group teleosts known so far possessed duplicated genomes. WGD therefore predates both the origin of proposed key innovations of the teleost skeleton and the onset of substantial morphological diversification in the clade. Moreover, the early occurrence of WGD allowed considerable time for postduplication reorganization prior to the origin of the teleost crown group. This suggests at most an indirect link between WGD and evolutionary success, with broad implications for the relationship between genomic architecture and large-scale evolutionary patterns in the vertebrate Tree of Life.

Whole-genome duplication (WGD) has occurred independently in multiple lineages of plants, fungi, and animals (1–3). This represents a major change to genomic architecture, with hypothesized impacts on evolutionary diversification (4, 5) caused by the origin of new gene functions from duplicate copies, expanding the genetic toolbox available for evolutionary “tinkering” (6). However, despite its mechanistic plausibility, this hypothesis is so far supported by only limited and contradictory empirical evidence (7–10). Teleost fishes—comprising more than one-half of modern vertebrates—are a key example, with their spectacular variety of form and kind (ranging from eels to seahorses) often viewed as prima facie evidence for the role of WGD in triggering evolutionary diversification (6, 11). Teleosts also show an incredible diversity of genome biology, demonstrating particularly high rates of evolution of protein-coding genes (12) and noncoding elements (13), a broad range of genome sizes including the smallest known in vertebrates (14), and multiple polyploid lineages (15).The genome of all living teleosts derives from an ancient WGD event that occurred before the last common ancestor of modern species (16). Additional duplication events occurred more recently in several teleost subgroups (9, 17) but are not generally proposed as drivers of diversification (9). Studies of the role of WGD in contributing to teleost diversity so far have analyzed the distribution of species richness among extant lineages and morphometric data for fossil phenotypes, with potentially conflicting results: extant teleosts have high rates of lineage diversification compared to other ray-finned fishes (7), but early fossil members of the teleost crown group do not show increased rates of morphological evolution (18).Molecular phylogenetic studies indicate that WGD occurred on the teleost stem lineage: after the divergence of teleosts from their extant sister taxon (Holostei) but before the most recent common ancestor of all living teleosts (19, 20). However, these bounds encompass a large phylogenetic diversity of extinct groups that diverged during an interval of 50 to 100 million y, from the initial origin of the teleost total group by the Triassic (21), up to the first appearance of crown-group teleosts in the Late Jurassic (18, 22). Molecular-clock estimates provide only broad constraints on the precise timing of duplication [316 to 226 Ma (23); ∼310 Ma (24)] and offer no information on its phylogenetic position on the teleost stem lineage. The imprecision of these estimates and the sometimes-considerable incongruence of molecular clocks with the teleost fossil record question the reliability of these inferences in the absence of further evidence.Patterns of genome-size evolution on the teleost stem lineage could provide alternative and independent evidence on the timing and phylogenetic position of the teleost WGD. However, stem lineages, by definition, comprise entirely extinct species that are known only from fossils, for which genomic data are absent. Nevertheless, some information about vertebrate genome size is preserved within fossil bone (25–27). Living organisms show a positive correlation between cell size and genome size (28–30), such that the volumes of bone cell spaces (osteocyte lacunae) allow estimates of genome size. This relationship has been demonstrated in ray-finned fishes, including teleosts, and is predictive for large-scale variation in genome size (31). The precision of this approach is sufficient for inferring the large change (presumably, doubling) of genome size involved in WGD (31). Here, we use this relationship to trace the evolution of genome size in extinct ray-finned fishes using osteocyte lacuna volumes as a proxy for genome size. Our sample includes a broad range of stem- and crown-group teleosts, providing information on patterns of teleost genome-size evolution during the deep evolutionary history of the teleost total group.Three-dimensional measurement of fossil bone cell spaces with μm-scale diameters presents considerable technical challenges. We used propagation phase contrast synchrotron radiation X-ray microcomputed tomography (PPC-SRµCT) to address this, collecting standardized measurements of osteocyte lacuna volumes for 61 fossil ray-finned fish species ranging from 2.5 to 252 million y in age (SI Appendix, section I). This fossil evidence is complemented by data from a previous study including 34 modern ray-finned fish species with known genome sizes (31). Our fossil sample includes all major groups of stem-group teleosts, members of both living and extinct lineages within the teleost crown group, and several nonteleost ray-finned fishes. This sample allows us to estimate relative genome sizes in extinct groups, providing information on the absolute timing and specific phylogenetic position of the teleost WGD as well as the timescale of postduplication reductions in genome size (24). Both statistical analysis and qualitative observations demonstrate the effectiveness of lacuna size for inferring large evolutionary increases in genome size: known polyploid lineages such as catostomids and salmonids, which underwent additional rounds of WGD, both show large osteocyte lacuna volumes compared to their close relatives (31).     

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.     

Osteocytes: central conductors of bone biology in normal and pathological conditions

Osteocytes are the most abundant and longest-living cells in the adult skeleton. For a long time, osteocytes were considered static and inactive cells, but in recent years, it has been suggested that they represent the key responder to various stimuli that regulate bone formation and remodelling as well as one of the key endocrine regulators of bone metabolism. Osteocytes respond to mechanical stimuli by producing and secreting several signalling molecules, such as nitric oxide and prostaglandin E(2) , that initiate local bone remodelling. Moreover, they can control bone formation by modulating the WNT signalling pathway, an essential regulator of cell fate and commitment, as they represent the main source of sclerostin, a negative regulator of bone formation. Osteocytes can also act as an endocrine organ by releasing fibroblast growth factor 23 and several other proteins (DMP-1, MEPE, PHEX) that regulate phosphate metabolism. It has been demonstrated that various bone diseases are associated with osteocyte abnormalities, although it is not clear if these changes are the direct cause of the pathology or if they are secondary to the pathological changes in the bone microenvironment. Thus, a better understanding of these cells could offer exciting opportunities for new advances in the prevention and management of different bone diseases.     

骨微损伤、骨重建与代谢性骨病

骨微损伤能启动骨重建,骨重建障碍而导致微损伤积累可引发骨折。扫描电镜、同步加速器射线μ-CT和高分辨磁共振显像是研究骨微损伤的新方法,骨理化构成和年龄对微损伤发生和发展有重要影响,骨细胞在微损伤修复中起重要作用,骨微损伤研究有利于代谢性骨病防治。