The effect of mechanical strain on soft (cardiovascular) and hard (bone) tissues

Mechanical stress plays a pivotal role in developing and maintaining tissues functionalities. Cells are constantly subjected to strain and compressive forces that are sensed by specialized membrane mechanosensors and converted in biochemical signals able to differently influence cellular behavior in terms of surviving, differentiation and extracellular matrix remodeling. This review focuses on the effects of mechanical strain on soft and hard tissues.

Unexpectedly, different cells share almost the same membrane mechanosensors and the relative intracellular pathways, but to ultimately obtain very different biological effects. The events occurring in cardiovascular and bone tissues are treated in details, showing that integrins, cadherins, growth factor receptors and ions channels specifically expressed in the different tissues are the major actors of the sight. However, MAPkinases and RhoGTPases are mainly involved in the biochemical intracellular signaling directed to nuclear modifications.     

Bone tissue engineering: the role of interstitial fluid flow

It is well established that vascularization is required for effective bone healing. This implies that blood flow and interstitial fluid (ISF) flow are required for healing and maintenance of bone. The fact that changes in bone blood flow and ISF flow are associated with changes in bone remodeling and formation support this theory. ISF flow in bone results from transcortical pressure gradients produced by vascular and hydrostatic pressure, and mechanical loading. Conditions observed to alter flow rates include increases in venous pressure in hypertension, fluid shifts occurring in bedrest and microgravity, increases in vascularization during the injury-healing response, and mechanical compression and bending of bone during exercise. These conditions also induce changes in bone remodeling. Previously, we hypothesized that interstitial fluid flow in bone, and in particular fluid shear stress, serves to mediate signal transduction in mechanical loading- and injury-induced remodeling. In addition, we proposed that a lack or decrease of ISF flow results in the bone loss observed in disuse and microgravity. The purpose of this article is to review ISF flow in bone and its role in osteogenesis.     

谷氨酸信号通路及其在骨力学信号转导通路中潜在的功能

自在中枢神经系统中发现谷氨酸发挥功能以来,谷氨酸受体及其在突触内膜偶联的信号通路,就成为神经系统研究的重要内容。近年的研究显示,谷氨酸受体及其胞内信号通路在包括骨在内的非神经组织中表达和发挥功能,在骨细胞中有表达谷氨酸受体、转运子的证据,因而有假说认为谷氨酸成了骨中力学信号潜在的转导子,但还缺乏有利的证据支持。简要综述了谷氨酸信号通路及其在骨中的功能,并就其在骨力学信号转导中潜在的功能和作用机制进行了探讨。     

A mathematical model for mechanotransduction at the early steps of suture formation

Growth and patterning of craniofacial sutures is subjected to the effects of mechanical stress. Mechanotransduction processes occurring at the margins of the sutures are not precisely understood. Here, we propose a simple theoretical model based on the orientation of collagen fibres within the suture in response to local stress. We demonstrate that fibre alignment generates an instability leading to the emergence of interdigitations. We confirm the appearance of this instability both analytically and numerically. To support our model, we use histology and synchrotron X-ray microtomography and reveal the fine structure of fibres within the sutural mesenchyme and their insertion into the bone. Furthermore, using a mouse model with impaired mechanotransduction, we show that the architecture of sutures is disturbed when forces are not interpreted properly. Finally, by studying the structure of sutures in the mouse, the rat, an actinopterygian (Polypterus bichir) and a placoderm (Compagopiscis croucheri), we show that bone deposition patterns during dermal bone growth are conserved within jawed vertebrates. In total, these results support the role of mechanical constraints in the growth and patterning of craniofacial sutures, a process that was probably effective at the emergence of gnathostomes, and provide new directions for the understanding of normal and pathological suture fusion.     

Gradients of strain and strain rate in the hollow muscular organs of soft-bodied animals

The cylindrical shape of soft-bodied invertebrates is well suited to functions in skeletal support and locomotion, but may result in a previously unrecognized cost—large non-uniformities in muscle strain and strain rate among the circular muscle fibres of the body wall. We investigated such gradients of strain and strain rate in the mantle of eight long-finned squid Doryteuthis pealeii and two oval squid Sepioteuthis lessoniana. Transmural gradients of circumferential strain were present during all jets (n = 312); i.e. for a given change in the circumference of the outer surface of the mantle, the inner surface experienced a greater proportional change. The magnitude of the difference increased with the amplitude of the mantle movement, with circular muscle fibres at the inner surface of the mantle experiencing a total range of strains up to 1.45 times greater than fibres at the outer surface during vigorous jets. Differences in strain rate between the circular fibres near the inner versus the outer surface of the mantle were also present in all jets, with the greatest differences occurring during vigorous jetting. The transmural gradients of circumferential strain and strain rate we describe probably apply not only to squids and other coleoid cephalopods, but also to diverse soft-bodied invertebrates with hollow cylindrical or conical bodies and muscular organs.     

Basal metabolic rate is positively correlated with parental investment in laboratory mice

The assimilation capacity (AC) hypothesis for the evolution of endothermy predicts that the maternal basal metabolic rate (BMR) should be positively correlated with the capacity for parental investment. In this study, we provide a unique test of the AC model based on mice from a long-term selection experiment designed to produce divergent levels of BMR. By constructing experimental families with cross-fostered litters, we were able to control for the effect of the mother as well as the type of pup based on the selected lines. We found that mothers with genetically determined high levels of BMR were characterized by higher parental investment capacity, measured as the offspring growth rate. We also found higher food consumption and heavier visceral organs in the females with high BMR. These findings suggested that the high-BMR females have higher energy acquisition abilities. When the effect of the line type of a foster mother was controlled, the pup line type significantly affected the growth rate only in the first week of life, with young from the high-BMR line type growing more rapidly. Our results support the predictions of the AC model.     

Dermal bone in early tetrapods: a palaeophysiological hypothesis of adaptation for terrestrial acidosis

The dermal bone sculpture of early, basal tetrapods of the Permo-Carboniferous is unlike the bone surface of any living vertebrate, and its function has long been obscure. Drawing from physiological studies of extant tetrapods, where dermal bone or other calcified tissues aid in regulating acid-base balance relating to hypercapnia (excess blood carbon dioxide) and/or lactate acidosis, we propose a similar function for these sculptured dermal bones in early tetrapods. Unlike the condition in modern reptiles, which experience hypercapnia when submerged in water, these animals would have experienced hypercapnia on land, owing to likely inefficient means of eliminating carbon dioxide. The different patterns of dermal bone sculpture in these tetrapods largely correlates with levels of terrestriality: sculpture is reduced or lost in stem amniotes that likely had the more efficient lung ventilation mode of costal aspiration, and in small-sized stem amphibians that would have been able to use the skin for gas exchange.     

Leaf photosynthetic rate is correlated with biomass and grain production in grain sorghum lines

Significant genetic variation in leaf photosynthetic rate has been reported in grain sorghum [Sorghum biocolor (L.) Moench]. The relationships between leaf photosynthetic rates and total biomass production and grain yield remain to be established and formed the purpose of this experiment. Twenty two grain sorghum parent lines were tested in the field during the 1988 growing season under well-watered and water-limited conditions. Net carbon assimilation rates were measured at mid-day during the 30 day period from panicle initiation to head exertion on upper-most fully expanded leaves using a portable photosynthesis system (LI-6200). Total biomass and grain production were determined at physiological maturity. The lines exhibited significant genetic variation in leaf photosynthetic rate, total biomass production and grain yield. Significant positive correlations existed between leaf photosynthesis and total biomass and grain production under both well-watered and water-limited conditions. The results suggest that leaf photosynthetic rate measured prior to flowering is a good indicator of productivity in grain sorghum.     

NMDA型谷氨酸受体在骨祖细胞和成骨细胞表达并介导力学信号转导

目的：鉴定骨髓间充质干细胞D1和成骨细胞MC3T3-E1、MC3T3-E1亚克隆14是否表达NMDA型谷氨酸受体（NMDAR）,并初步探讨NMDAR是否参与力学信号转导。方法：采用RT—PCR技术、免疫荧光染色技术、蛋白免疫杂交技术和体外细胞循环拉伸装置,鉴定了上述3个细胞系中NMDAR的表达情况,并初步探讨了在MC3T3-E1亚克隆14细胞系中,NMDAR在力学信号转导中的可能作用。结果：3个细胞系均表达NMDA受体亚基1（NR1）和不同的亚基2（NR2A—NR2D）。细胞微丝骨架的破坏并没有阻断力学应变诱导的c-jun、C—fos的表达上调;而阻断NMDAR后,却抑制了力学应变诱导的c-jun、C—fos和成骨细胞特异的转录因子Cbfa1／Runx2的表达上调。结论：NMDAR在骨中表达并发挥功能,参与了骨的力学信号转导过程。     

Integrin-regulated secretion of interleukin 4: A novel pathway of mechanotransduction in human articular chondrocytes

Chondrocyte function is regulated partly by mechanical stimulation. Optimal mechanical stimulation maintains articular cartilage integrity, whereas abnormal mechanical stimulation results in development and progression of osteoarthritis (OA). The responses of signal transduction pathways in human articular chondrocytes (HAC) to mechanical stimuli remain unclear. Previous work has shown the involvement of integrins and integrin-associated signaling pathways in activation of plasma membrane apamin-sensitive Ca2+-activated K+ channels that results in membrane hyperpolarization of HAC after 0. 33 Hz cyclical mechanical stimulation. To further investigate mechanotransduction pathways in HAC and show that the hyperpolarization response to mechanical stimulation is a result of an integrin-dependent release of a transferable secreted factor, we used this response. Neutralizing antibodies to interleukin 4 (IL-4) and IL-4 receptor alpha inhibit mechanically induced membrane hyperpolarization and anti-IL-4 antibodies neutralize the hyperpolarizing activity of medium from mechanically stimulated cells. Antibodies to interleukin 1beta (IL-1beta) and cytokine receptors, interleukin 1 receptor type I and the common gamma chain/CD132 (gamma) have no effect on me- chanically induced membrane hyperpolarization. Chondrocytes from IL-4 knockout mice fail to show a membrane hyperpolarization response to cyclical mechanical stimulation. Mechanically induced release of the chondroprotective cytokine IL-4 from HAC with subsequent autocrine/paracrine activity is likely to be an important regulatory pathway in the maintenance of articular cartilage structure and function. Finally, dysfunction of this pathway may be implicated in OA.     

Effect of strain rate on the fracture behaviour of skin

The effect of strain rate on the stress-strain behaviour of skin is studied. It is observed that the plastic set in the skin is dependent on strain rate. The scanning electron micrographs of the fractured skin sample shows thicker fibrils and thinner one at low strain rates. The plastic flow is clearly brought out in the stress-strain curves at different strain rates. The stress relaxation behaviour at any given strain is clearly brought out in the 3-dimensional plot.     

Relationship of strain magnitude to morphological variation in the primate skull

In a comparative study of variation in primate skulls, Wood and Lieberman ([ 2001 ] Am. J. Phys. Anthropol. 116:13–25) proposed that a predictable relationship exists between in vivo bone‐strain magnitudes and the extent of morphological variation in skeletal structures. They hypothesized that regions subject to high strains are prone to enhanced levels of variation. Three questions are posed with respect to the plausibility of this hypothesis. First, does the proposed relationship hold at different levels of analysis (e.g., for more restricted anatomical regions in which large strain gradients are present)? Second, is the biomechanical rationale for the hypothesis sound, given the current understanding of bone biology? Third, is the hypothesis obviated by consideration of the functional matrix concept of skull development, in which osseous growth is posited to be governed by surrounding soft tissues (e.g., muscle and tendon) and developing spaces (e.g., the nasal capsule)? The different perspectives explored by these questions suggest that the validity of the hypothesis, despite having a defensible theoretical rationale, is likely to be context‐specific. A direct role for strain magnitude in conditioning morphological variation is difficult to demonstrate either comparatively or theoretically, and it is unlikely that a single strain threshold or interval can be directly associated with elevated variation in the skeleton. The conceptual framework of the functional matrix (which allows for independent growth among different regions of the skull) conceivably contravenes the premise of a uniform relationship of strain magnitude to morphological variability. Am J Phys Anthropol, 2003. © 2003 Wiley‐Liss, Inc.     

Bone morphogenetic protein receptor signaling is necessary for normal murine postnatal bone formation

Functions of bone morphogenetic proteins (BMPs) are initiated by signaling through specific type I and type II serine/threonine kinase receptors. In previous studies, we have demonstrated that the type IB BMP receptor (BMPR-IB) plays an essential and specific role in osteoblast commitment and differentiation. To determine the role of BMP receptor signaling in bone formation in vivo, we generated transgenic mice, which express a truncated dominant-negative BMPR-IB targeted to osteoblasts using the type I collagen promoter. The mice are viable and fertile. Tissue-specific expression of the truncated BMPR-IB was demonstrated. Characterization of the phenotype of these transgenic mice showed impairment of postnatal bone formation in 1-mo-old homozygous transgenic mice. Bone mineral density, bone volume, and bone formation rates were severely reduced, but osteoblast and osteoclast numbers were not significantly changed in the transgenic mice. To determine whether osteoblast differentiation is impaired, we used primary osteoblasts isolated from the transgenic mice and showed that BMP signaling is blocked and BMP2-induced mineralized bone matrix formation was inhibited. These studies show the effects of alterations in BMP receptor function targeted to the osteoblast lineage and demonstrate a necessary role of BMP receptor signaling in postnatal bone growth and bone formation in vivo.     

Osteoblast migration in vertebrate bone

Bone formation, for example during bone remodelling or fracture repair, requires mature osteoblasts to deposit bone with remarkable spatial precision. As osteoblast precursors derive either from circulation or resident stem cell pools, they and their progeny are required to migrate within the three‐dimensional bone space and to navigate to their destination, i.e. to the site of bone formation. An understanding of this process is emerging based on in vitro and in vivo studies of several vertebrate species. Receptors on the osteoblast surface mediate cell adhesion and polarization, which induces osteoblast migration. Osteoblast migration is then facilitated along gradients of chemoattractants. The latter are secreted or released proteolytically by several cell types interacting with osteoblasts, including osteoclasts and vascular endothelial cells. The positions of these cellular sources of chemoattractants in relation to the position of the osteoblasts provide the migrating osteoblasts with tracks to their destination, and osteoblasts possess the means to follow a track marked by multiple chemoattractant gradients. In addition to chemotactic cues, osteoblasts sense other classes of signals and utilize them as landmarks for navigation. The composition of the osseous surface guides adhesion and hence migration efficiency and can also provide steering through haptotaxis. Further, it is likely that signals received from surface interactions modulate chemotaxis. Besides the nature of the surface, mechanical signals such as fluid flow may also serve as navigation signals for osteoblasts. Alterations in osteoblast migration and navigation might play a role in metabolic bone diseases such as osteoporosis.     

Bone histology of claudiosaurus germaini (reptilia,claudiosauridae) and the problem of pachyostosis in aquatic tetrapods

Histological study of the skeleton of Claudiosaurus germaini reveals extensive pachyostosis. This feature results from the filling of intra‐osseous cavities by centripetal, endosteal deposits and occurs in conjunction with an intense remodelling of the bones by resorption and re‐deposition. Epiphyseal calcified cartilages are rapidly and entirely resorbed. Extensive pachyostosis suggests that Claudiosaurus was an aquatic reptile. However, the pachyostotic condition in this genus appears histogenetically quite different from the common type of pachyostosis observed in other aquatic tetrapods. Hence, it probably had a distinct physiological significance.     

Regulation of tenascin expression in bone

Tenascins regulate cell interaction with the surrounding pericellular matrix. Within bone, tenascins C and W influence osteoblast adhesion and differentiation, although little is known about the regulation of tenascin expression. In this study we examined the effect of osteogenic differentiation, bone morphogenetic protein (BMP) and Wnt growth factors, and mechanical loading on tenascin expression in osteogenic cells. Osteogenic differentiation increased tenascin C (TnC), and decreased tenascin W (TnW), expression. Both growth factors and mechanical loading increased both TnC and TnW expression, albeit via distinct signaling mechanisms. Both BMP-2 and Wnt5a induction of tenascin expression were mediated by MAP kinases. These data establish a role for BMP, Wnts, and mechanical loading in the regulation of tenascin expression in osteoblasts.