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Integrins and cytoskeleton play important role in the conversion of mechanical signals into intracellular biochemical signals followed by physiological or pathological responses. At the same time, the system of extracellular matrix (ECM)-integrins-cytoskeleton (CSK) axis is in close connection with ion channels and signal transduction, and they interact with each other.
Analysis of cellular mechanotransduction, the mechanism by which cells convert mechanical signals into biochemical responses, has focused on identification of critical mechanosensitive molecules and cellular components. Stretch-activated ion channels, caveolae, integrins, cadherins, growth factor receptors, myosin motors, cytoskeletal filaments, nuclei, extracellular matrix, and numerous other structures and signaling molecules have all been shown to contribute to the mechanotransduction response. However, little is known about how these different molecules function within the structural context of living cells, tissues, and organs to produce the orchestrated cellular behaviors required for mechanosensation, embryogenesis, and physiological control. Recent work from a wide range of fields reveals that organ, tissue, and cell anatomy are as important for mechanotransduction as individual mechanosensitive proteins and that our bodies use structural hierarchies (systems within systems) composed of interconnected networks that span from the macroscale to the nanoscale in order to focus stresses on specific mechanotransducer molecules. The presence of isometric tension (prestress) at all levels of these multiscale networks ensures that various molecular scale mechanochemical transduction mechanisms proceed simultaneously and produce a concerted response. Future research in this area will therefore require analysis, understanding, and modeling of tensionally integrated (tensegrity) systems of mechanochemical control.
At present, infrasound (0-20 Hz) and low-frequency noise (20-500 Hz) (ILFN, 0-500 Hz) are agents of disease that go unchecked. Vibroacoustic disease (VAD) is a whole-body pathology that develops in individuals excessively exposed to ILFN. VAD has been diagnosed within several professional groups employed within the aeronautical industry, and in other heavy industries. However, given the ubiquitous nature of ILFN and the absence of legislation concerning ILFN, VAD is increasingly being diagnosed among members of the general population, including children. VAD is associated with the abnormal growth of extra-cellular matrices (collagen and elastin), in the absence of an inflammatory process. In VAD, the end-product of collagen and elastin growth is reinforcement of structural integrity. This is seen in blood vessels, cardiac structures, trachea, lung, and kidney of both VAD patients and ILFN-exposed animals. VAD is, essentially, a mechanotransduction disease. Inter- and intra-cellular communication is achieved through both biochemical and mechanotranduction signalling. When the structural components of tissue are altered, as is seen in ILFN-exposed specimens, the mechanically mediated signalling is, at best, impaired. Common medical diagnostic tests, such as EKG, EEG, as well as many blood chemistry analyses, are based on the mal-function of biochemical signalling processes. VAD patients typically present normal values for these tests. However, when echocardiography, brain MRI or histological studies are performed, where structural changes can be identified, all consistently show significant changes in VAD patients and ILFN-exposed animals. Frequency-specific effects are not yet known, valid dose-responses have been difficult to identify, and large-scale epidemiological studies are still lacking.
Physical forces play an important role in modulating cell function and shaping tissue structure. Mechanotransduction, the process by which cells transduce physical force-induced signals into biochemical responses, is critical for mediating adaptations to mechanical loading in connective tissues. While much is known about mechanotransduction in cells involving forces delivered through extracellular matrix proteins and integrins, there is limited understanding of how mechanical signals are propagated through the interconnected cellular networks found in tissues and organs. We propose that intercellular mechanotransduction is a critical component for achieving coordinated remodeling responses to force application in connective tissues. We examine here recent evidence on different pathways of intercellular mechanotransduction and suggest a general model for how multicellular structures respond to mechanical loading as an integrated unit.
Physical forces of gravity, hemodynamic stresses, and movement play a critical role in tissue development. Yet, little is known about how cells convert these mechanical signals into a chemical response. This review attempts to place the potential molecular mediators of mechanotransduction (e.g. stretch-sensitive ion channels, signaling molecules, cytoskeleton, integrins) within the context of the structural complexity of living cells. The model presented relies on recent experimental findings, which suggests that cells use tensegrity architecture for their organization. Tensegrity predicts that cells are hard-wired to respond immediately to mechanical stresses transmitted over cell surface receptors that physically couple the cytoskeleton to extracellular matrix (e.g. integrins) or to other cells (cadherins, selectins, CAMs). Many signal transducing molecules that are activated by cell binding to growth factors and extracellular matrix associate with cytoskeletal scaffolds within focal adhesion complexes. Mechanical signals, therefore, may be integrated with other environmental signals and transduced into a biochemical response through force-dependent changes in scaffold geometry or molecular mechanics. Tensegrity also provides a mechanism to focus mechanical energy on molecular transducers and to orchestrate and tune the cellular response.
Fluid flow has been shown to be a potent physical stimulus in the regulation of bone cell metabolism. In addition to membrane shear stress, loading-induced fluid flow will enhance chemotransport due to convection or mass transport thereby affecting the biochemical environment surrounding the cell. This study investigated the role of oscillating fluid flow induced shear stress and chemotransport in cellular mechanotransduction mechanisms in bone. Intracellular calcium mobilization and prostaglandin E(2) (PGE(2)) production were studied with varying levels of shear stress and chemotransport. In this study MC3T3-E1 cells responded to oscillating fluid flow with both an increase in intracellular calcium concentration ([Ca(2+)](i)) and an increase in PGE(2) production. These fluid flow induced responses were modulated by chemotransport. The percentage of cells responding with an [Ca(2+)](i) oscillation increased with increasing flow rate, as did the production of PGE(2). In addition, depriving the cells of nutrients during fluid flow resulted in an inhibition of both [Ca(2+)](i) mobilization and PGE(2) production. These data suggest that depriving the cells of a yet to be determined biochemical factor in media affects the responsiveness of bone cells even at a constant peak shear stress. Chemotransport alone will not elicit a response, but it appears that sufficient nutrient supply or waste removal is needed for the response to oscillating fluid flow induced shear stress.
Mechanoreception and subsequent cellular/molecular mechanisms of signal transduction pathways in response to mechanical stresses, including hemodynamic factors, passive stretching, and exercise, are ubiquitous in living organisms. Of these, the cardiovascular system involving the heart and blood vessels is known to be particularly sensitive to mechanical stimuli, for example, stretching and intraluminal pressurization, which might mimic an acute and/or chronic change in blood pressure and flow, induce a variety of responses including contraction, activation of various kinases and ionic channels, production of vasoactive substances, gene expression, and phenotype changes. We have started to clarify the mechanisms underlying this basic principle in the cardiovascular system as it is now generally considered that obesity and a lack of exercise are serious risk factors for cardiovascular diseases such as hypertension, atherosclerosis, and type 2 diabetes. We further extended our research field of mechanotransduction into adipocytes, skeletal muscle cells, and pancreatic beta cells, all of which are related to the core concerns in cardiovascular disease, including the so-called metabolic syndrome. In the present article, we discuss briefly the prologue to our study of mechanotransduction and several topics in the recent progress in this interesting area. We also emphasize that it is important to recognize biomechanical factors and control them not only for improvement in our knowledge of health and disease but also for the development of new drugs.
This article is a summary of a lecture presented at a symposium on "Mechanics and Chemistry of Biosystems" in honor of Professor Y.C. Fung that convened at the University of California, Irvine in February 2004. The article reviews work from our laboratory that focuses on the mechanism by which mechanical and chemical signals interplay to control how individual cells decide whether to grow, differentiate, move, or die, and thereby promote pattern formation during tissue morphogenesis. Pursuit of this challenge has required development and application of new microtechnologies, theoretical formulations, computational models and bioinformatics tools. These approaches have been used to apply controlled mechanical stresses to specific cell surface molecules and to measure mechanical and biochemical responses; to control cell shape independently of chemical factors; and to handle the structural, hierarchical and informational complexity of living cells. Results of these studies have changed our view of how cells and tissues control their shape and mechanical properties, and have led to the discovery that integrins and the cytoskeleton play a central role in cellular mechanotransduction. Recognition of these critical links between mechanics and cellular biochemistry should lead to novel strategies for the development of new drugs and engineered tissues, as well as biomimetic microdevices and nanotechnologies that more effectively function within the context of living tissues.
Tendons are able to respond to mechanical forces by altering their structure, composition, and mechanical properties--a process called tissue mechanical adaptation. The fact that mechanical adaptation is effected by cells in tendons is clearly understood; however, how cells sense mechanical forces and convert them into biochemical signals that ultimately lead to tendon adaptive physiological or pathological changes is not well understood. Mechanobiology is an interdisciplinary study that can enhance our understanding of mechanotransduction mechanisms at the tissue, cellular, and molecular levels. The purpose of this article is to provide an overview of tendon mechanobiology. The discussion begins with the mechanical forces acting on tendons in vivo, tendon structure and composition, and its mechanical properties. Then the tendon's response to exercise, disuse, and overuse are presented, followed by a discussion of tendon healing and the role of mechanical loading and fibroblast contraction in tissue healing. Next, mechanobiological responses of tendon fibroblasts to repetitive mechanical loading conditions are presented, and major cellular mechanotransduction mechanisms are briefly reviewed. Finally, future research directions in tendon mechanobiology research are discussed.
Bone undergoes continuous remodeling in response to mechanical loading. However, the underlying mechanisms by which bone cells respond to their changing mechanical environment, that is, strain in the load-bearing matrix or fluid flow through the canalicular network, are not well understood. It has been established in vitro that bone cells respond differently to substrate strain and fluid shear stress treatments. Uncovering the mechanical basis of these differences represents a significant challenge to our understanding of cellular mechanotransduction and bone remodeling. To investigate this problem, we developed a biomechanical model of an adherent cell, to test the hypothesis that bone cells respond differently to 0.6 Pa fluid shear stress and 1,000 mu(epsilon) substrate strain stimulation because of qualitative and quantitative differences in the cellular deformation caused. Fluid shear stress loading conditions resulted in maximum displacements at the apical surface of the cell approximately 8 times higher than those due to strain at the cell-substrate interface and also caused higher stressing of all parts of the cell. Significantly, this shows that the deforming effects of fluid shear stress and strain on a cellular level are qualitatively different, which may provide a basis for explaining differences in bone cell responses to both stimuli as reported in several studies. Although our approach to modeling the morphology and complex physical environment of an adherent cell is certainly simplified, our results do show independent roles for fluid flow and strain as mechanical stimuli and highlight the importance of deformation on a cellular level in bone physiology.
The current focus of medicine on molecular genetics ignores the physical basis of disease even though many of the problems that lead to pain and morbidity, and bring patients to the doctor's office, result from changes in tissue structure or mechanics. The main goal of this article is therefore to help integrate mechanics into our understanding of the molecular basis of disease. This article first reviews the key roles that physical forces, extracellular matrix and cell structure play in the control of normal development, as well as in the maintenance of tissue form and function. Recent insights into cellular mechanotransduction--the molecular mechanism by which cells sense and respond to mechanical stress--also are described. Re-evaluation of human pathophysiology in this context reveals that a wide range of diseases included within virtually all fields of medicine and surgery share a common feature: their etiology or clinical presentation results from abnormal mechanotransduction. This process may be altered by changes in cell mechanics, variations in extracellular matrix structure, or by deregulation of the molecular mechanisms by which cells sense mechanical signals and convert them into a chemical or electrical response. Molecules that mediate mechanotransduction, including extracellular matrix molecules, transmembrane integrin receptors, cytoskeletal structures and associated signal transduction components, may therefore represent targets for therapeutic intervention in a variety of diseases. Insights into the mechanical basis of tissue regulation also may lead to development of improved medical devices, engineered tissues, and biologically-inspired materials for tissue repair and reconstruction.
Acupuncture needle rotation has been previously shown to cause specific mechanical stimulation of subcutaneous connective tissue. This study uses acupuncture to investigate the role of mechanotransduction-based mechanisms in mechanically-induced cytoskeletal remodeling. The effect of acupuncture needle rotation was quantified by morphometric analysis of mouse tissue explants imaged with confocal microscopy. Needle rotation induced extensive fibroblast spreading and lamellipodia formation within 30 min, measurable as an increased in cell body cross sectional area. The effect of rotation peaked with two needle revolutions and decreased with further increases in rotation. Significant effects of rotation were present throughout the tissue, indicating the presence of a response extending laterally over several centimeters. The effect of rotation with two needle revolutions was prevented by pharmacological inhibitors of actomyosin contractility (blebbistatin), Rho kinase (Y-27632 and H-1152), and Rac signaling. The active cytoskeletal response of fibroblasts demonstrated in this study constitutes an important step in understanding cellular mechanotransduction responses to externally applied mechanical stimuli in whole tissue, and supports a previously proposed model for the mechanism of acupuncture involving connective tissue mechanotransduction.
Mechanotransduction--the process by which mechanical forces are converted into changes of intracellular biochemistry--is critical for normal cell and tissue function. Integrins facilitate mechanochemical conversion by transferring physical forces from the extracellular matrix, across the cell surface, and to cytoskeletal-associated proteins within focal adhesions. It is likely that force alters biochemistry at these sites by altering molecular binding affinities of a subset of focal adhesion proteins, but this has been difficult to quantify within living cells. Here, we describe how the fluorescence recovery after photobleaching (FRAP) technique can be adapted and used in conjunction with mathematical models to directly measure force-dependent alterations in molecular binding and unbinding rate constants of individual focal adhesion proteins in situ. We review these recent findings, and discuss the strengths and limitations of this approach for analysis of mechanochemical signaling in focal adhesions and other cellular structures. The ability to quantify molecular binding rate constants in the physical context of the living cytoplasm should provide new insight into the molecular basis of cellular mechanotransduction. It also may facilitate future efforts to bridge biological experimentation and mathematical modeling in our quest for a systems biology level description of cell regulation.
The periodic incorporation of advances in the biomedical, bioengineering, and computer sciences allow the creation of increasingly more comprehensive revisions of the functional matrix hypothesis. Inclusion of two topics, (1) the mechanisms of cellular mechanotransduction, and (2) biologic network theory, permit this latest revision; presented here in two interrelated articles. In this first article, the several possible types of intracellular processes of mechanotransduction are described. These translate the informational content of a periosteal functional matrix stimulus into a skeletal unit (bone) cell signal. The correlation between the strengths of the endogenous electrical fields produced by muscle skeletal muscle activity, and those to which bone cells maximally respond are stressed. Further, a physical chain of macromolecular levers, connecting the extracellular matrix to the bone cell genome is described, suggesting another means of epigenetic regulation of the bone cell genome, including its phenotypic expression.
The skeleton's primary mechanical function is to provide rigid levers for muscles to act against as they hold the body upright in defiance of gravity. Many bones are exposed to thousands of repetitive loads each day. During growth and development, the skeleton optimizes its architecture by subtle adaptations to these mechanical loads. The mechanisms for adaptation involve a multistep process of cellular mechanotransduction including: mechanocoupling - conversion of mechanical forces into local mechanical signals, such as fluid shear stresses, that initiate a response by bone cells; biochemical coupling - transduction of a mechanical signal to a biochemical response involving pathways within the cell membrane and cytoskeleton; cell-to-cell signaling from the sensor cells (probably osteocytes and bone lining cells) to effector cells (osteoblasts or osteoclasts) using prostaglandins and nitric oxide as signaling molecules; and effector response - either bone formation or resorption to cause appropriate architectural changes. These architectural changes tend to adjust and improve the bone structure to its prevailing mechanical environment. Structural changes can be predicted, to some extent, by mathematical formulas derived from three fundamental rules: (1) bone adaptation is driven by dynamic, rather than static, loading; (2) extending the loading duration has a diminishing effect on further bone adaptation; (3) bone cells accommodate to a mechanical loading environment, making them less responsive to routine or customary loading signals.
Mechanical stretching of connective tissue occurs with normal movement and postural changes, as well as treatments including physical therapy, massage and acupuncture. Connective tissue fibroblasts were recently shown to respond actively to short-term mechanical stretch (minutes to hours) with reversible cytoskeletal remodeling, characterized by extensive cell spreading and lamellipodia formation. In this study, we have examined the effect of tissue stretch on the distribution of alpha- and beta-actin in subcutaneous tissue fibroblasts ex vivo. Normal fibroblasts uniformly exhibited alpha-smooth muscle actin (alpha-SMA) immunoreactivity. Unlike cultured fibroblasts and smooth muscle cells, alpha-SMA in these fibroblasts was not in F-actin form (indicated by lack of phalloidin co-localization) nor was it organized into distinct stress fibers. The lack of stress fibers and fibronexus was confirmed by electron microscopy, indicating that these cells were not myofibroblasts. In unstretched tissue, the pattern of alpha-actin was diffuse and granular. With tissue stretch (30 min), alpha-actin formed a star-shaped pattern centered on the nucleus, while beta-actin extended throughout the cytoplasm including lamellipodia and cell cortex. This dual response pattern of alpha- and beta-actin may be an important component of cellular mechanotransduction mechanisms relevant to physiologic and therapeutic mechanical forces applied to connective tissue.
The capacity of bone tissue to alter its mass and structure in response to mechanical demands has long been recognized but the cellular mechanisms involved remained poorly understood. Bone not only develops as a structure designed specifically for mechanical tasks, but it can adapt during life toward more efficient mechanical performance. Mechanical adaptation of bone is a cellular process and needs a biological system that senses the mechanical loading. The loading information must then be communicated to the effector cells that form new bone or destroy old bone. The in vivo operating cell stress derived from bone loading is likely the flow of interstitial fluid along the surface of osteocytes and lining cells. The response of bone cells in culture to fluid flow includes prostaglandin (PG) synthesis and expression of prostaglandin G/H synthase inducible cyclooxygenase (COX-2). Cultured bone cells also rapidly produce nitric oxide (NO) in response to fluid flow as a result of activation of endothelial nitric oxide synthase (ecNOS), which enzyme also mediates the adaptive response of bone tissue to mechanical loading. Earlier studies have shown that the disruption of the actin-cytoskeleton abolishes the response to stress, suggesting that the cytoskeleton is involved in cellular mechanotransduction. Microgravity, or better near weightlessness, is associated with the loss of bone in astronauts, and has catabolic effects on mineral metabolism in bone organ cultures. This might be explained as resulting from an exceptional form of disuse under near weightlessness conditions. However, under near weightlessness conditions the assembly of cytoskeletal elements may be altered since it has been shown that the direction of the gravity vector determines microtubular pattern formation in vivo. We found earlier that the transduction of mechanical signals in bone cells also involves the cytoskeleton and is related to PGE2 production. Therefore it is possible that the mechanosensitivity of bone cells is altered under near weightlessness conditions, and that this abnormal mechanosensation contributes to disturbed bone metabolism observed in astronauts. In our current project for the International Space Station, we wish to test this hypothesis experimentally using an in vitro model. The specific aim of our research project is to test whether near weightlessness decreases the sensitivity of bone cells for mechanical stress through a decrease in early signaling molecules (NO, PGs) that are involved in the mechanical loading-induced osteogenic response. Bone cells are cultured with or without gravity prior to and during mechanical loading, using our modified in vitro oscillating fluid flow apparatus. In this "FlowSpace" project we are developing a cell culture module that is used to provide further insight in the mechanism of mechanotransduction in bone.
Bone cells, in particular osteocytes, are extremely sensitive to mechanical stress, a quality that is probably linked to the process of mechanical adaptation (Wolff's law). The in vivo operating cell stress derived from bone loading is likely a flow of an interstitial fluid along the surface of the osteocytes and lining cells. The response of bone cells in culture to fluid flow includes prostaglandin synthesis and expression of inducible prostaglandin G/H synthase (PGHS-2 or inducible cyclooxygenase, COX-2), an enzyme that mediates the induction of bone formation by mechanical loading in vivo. Disruption of the actin-cytoskeleton abolishes the response to stress, suggesting that the cytoskeleton is involved in cellular mechanotransduction. Microgravity has catabolic effects on the skeleton of astronauts, as well as on mineral metabolism in bone organ cultures. This might be explained simply as resulting from an exceptional form of disuse under weightlessness conditions. However, under microgravity conditions, the assembly of cytoskeletal elements may be altered, as gravity has been shown to determine the pattern of microtubular orientation assembled in vitro. Therefore, it is possible that the mechanosensitivity of bone cells is altered under microgravity conditions, and that this abnormal mechanosensation contributes to the disturbed bone metabolism observed in astronauts. In vitro experiments on the International Space Station should test this hypothesis experimentally.