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Kamkin A, Kiseleva I, editors. Mechanosensitivity in Cells and Tissues. Moscow: Academia; 2005.

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Mechanosensitivity in Cells and Tissues.

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Functional Roles of Mechanosensitive Ion Channels, ß1 Integrins and Kinase Cascades in Chondrocyte Mechanotransduction

, , , , , and .

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,1,* ,1 ,1 ,2 ,3 and 4.

1 Faculty of Veterinary Science, The University of Liverpool, Liverpool L69 7ZJ, United Kingdom
2 Laboratory of Developmental Biology, Department of Biochemistry and Molecular Biology, University of La Laguna, 38206 La Laguna, Tenerife, Spain
3 Charité University Medical School Berlin, Institute of Anatomy, Department of Cell and Neurobiology, Campus Benjamin Franklin, D-14195 Berlin, Germany
4 Ludwig-Maximilians-University Munich, Faculty of Medicine, Institute of Anatomy, Musculoskeletal Research Group, 80336 Munich, Germany
*Corresponding author: Ali Mobasheri, D.Phil. Connective Tissue Research Group, Faculty of Veterinary Science, University of Liverpool, Liverpool L69 7ZJ, United Kingdom, Phone: +44 -151-7944284, Telefax: +44 -151-7944243, e-mail: ku.ca.looprevil@irehsabom.a

Sensitivity to biomechanical signals and adaptive responses to such stimuli are fundamental properties of articular cartilage. Chondrocytes are specialized cells that utilize mechanical signals to synthesize a mechanically unique extracellular matrix capable of withstanding high loads and shear stresses. Chondrocytes undergo changes in shape and volume when load induces matrix deformation. Changes in hydrostatic pressure, ionic and osmotic composition, interstitial fluid and streaming potentials are sensed by chondrocytes. Responses to these stimuli alter gene expression, matrix composition and biomechanical competence. In this article we focus on the role of mechanosensitive ion channels, β1-integrins and mitogen-activated protein (MAP) kinase kinase pathways in chondrocyte mechanotransduction.

Introduction

Biomechanical signals regulate the growth, development and function of a variety of cardiovascular and musculoskeletal tissues [14, 15, 16]. In the hypertensive circulatory system elevated mechanical pressure leads to increased smooth muscle thickness and strength in the vascular walls and in the myocardium [11, 40, 47]. When combined with endocrine signals, mechanical stimulation is capable of increasing tissue mass and promoting hyperplasia [60, 70]. Mechanical forces are important for the development, maintenance and remodelling of load bearing connective tissues in the musculoskeletal system. These tissues include articular cartilage [18, 23], bone [9, 43, 55], intervertebral disks lying between vertebral bodies in the spine, tendon [65] and ligament [39, 54].

Chondrocytes as mechanotransducers in cartilage

Chondrocytes are highly specialized cells that can detect and respond to the applied load by altering their metabolic state through a process known as mechanotransduction [18, 25, 45]. Mechanotransduction is the dynamic process that allows chondrocytes to quantitatively modulate the rates of matrix synthesis and degradation and alter the composition of the extracellular matrix. The mechanical environment of articular chondrocytes has a profound influence on the health and normal function of the articulating joint [21]. Chondrocytes are excellent sensors of mechanical, ionic and osmotic signals and respond to these signals in coordination with other environmental, hormonal and genetic factors to regulate metabolic activity (Fig. 1) [34].

Figure 1. The effects of mechanical load on the physical environment of human articular chondrocytes.

Figure 1

The effects of mechanical load on the physical environment of human articular chondrocytes.

This metabolic regulation is essential to the health, structural integrity and functional performance of articulating joints [2]. The mechanical responsiveness of cartilage provides the mechanisms by which chondrocytes can alter the three-dimensional structure, metabolism and extracellular matrix composition of the tissue to meet the physical demands of the mobile vertebrate organism. In osteoarthritis where the structure and function of articular cartilage has already been compromised by catabolic factors promoting the activity of matrix degrading metalloproteinases (collagenases) and aggrecanase, inappropriate mechanical signals may contribute to the progression of degenerative changes in the extracellular matrix thus exacerbating the detrimental effects of the existing pathology [3, 22, 42]. The sequence of biomechanical and biochemical events that occur following mechanical stimulation in chondrocytes is poorly understood [21, 29, 30]. A more in depth appreciation of the signalling and regulatory pathways activated during mechanical signal transduction in normal articular cartilage is pre-requisite to understanding the abnormal mechanotransduction that is thought to occur in a degenerate cartilage matrix in disease states such as osteoarthritis.

Mechanotransduction in cartilage

Dynamic stress on cartilage produces increases in intracellular cAMP [57, 63] and proteoglycan synthesis [41, 45] and a decrease in DNA synthesis. In contrast static, continuous compression has been shown to produce the opposite effect [18]. The mode of mechanotransduction causing these changes in metabolism is not fully understood but simple mechanical distortion of the chondrocyte membrane and nucleus [22], changes in membrane potential [68], electric stimuli from piezoelectric effects and streaming potentials [20, 28, 38] and physicochemical effects involving changes in matrix water content, ion concentrations and pH [34, 38] have all been suggested to be involved (Figures 2 and 3). These mechanisms may not be mutually exclusive and it is likely that all of these affect the chondrocyte plasma membrane through mechanical distortion of the pericellular matrix.

Figure 2. Schematic illustration of mechano-electrochemical responses in chondrocytes under mechanical load and the interaction between the extracellular matrix and chondrocytes.

Figure 2

Schematic illustration of mechano-electrochemical responses in chondrocytes under mechanical load and the interaction between the extracellular matrix and chondrocytes. Δπ* represents changes in osmotic pressure and ΔΨ (more...)

Figure 3. Schematic illustration of 3-dimensional cartilage structure and chondrocyte distribution in various zones, and the interrelationship between tissue composition, mechano-electrochemical signals and biosynthetic activities (adapted from [38]).

Figure 3

Schematic illustration of 3-dimensional cartilage structure and chondrocyte distribution in various zones, and the interrelationship between tissue composition, mechano-electrochemical signals and biosynthetic activities (adapted from [38]).

Chondrocyte matrix interactions

Mechanotransduction in articular cartilage may be resolved into extracellular components, followed by plasma membrane alterations and intracellular signalling events that result in changes in gene expression and an altered cellular response [27]. Cell and nucleus deformation and alterations in hydrostatic pressure, ionic and osmotic composition, interstitial water and streaming potentials constitute the primary component of mechanotransduction [21, 30]. This is then followed by physical changes in the mechanoreceptor complexes, activation of stretch-responsive ion channels and changes in the chondrocyte membrane potential [68, 69]. Changes in intracellular ion concentrations, primarily Na+ and then Ca2+ result in generation of calcium waves, release of other intracellular messengers (inositol triphosphates, diacylglycerol and Ca2+ from intracellular stores) initiating phosphorylation events and activating kinase cascades [48]. The kinase cascades thus activated play fundamental roles in maintaining the phenotype of chondrocytes by regulating the expression and activity of universal and chondrocyte specific transcription factors (i.e. Sox genes; [31, 32]) that turn on chondrocyte specific genes important for the differentiation, growth and survival of these cells in the extracellular matrix [51].

The pericellular matrix of chondrocytes defines the physicochemical environment of the chondrocytes and physically interacts with the chondrocyte through cell surface receptors including integrins CD44, annexin V and other related receptors which bind to collagens, fibronectin, laminin, vitronectin and hyaluronan [33, 53, 66]. Since the pericellular matrix completely surrounds the chondrocyte, it has been proposed that any mechanical or biochemical signal perceived by the chondrocyte is influenced by the structural and functional composition of this region [21, 34]. There is growing evidence that the primary function of the pericellular matrix is concerned with biomechanical performance [19]. The macromolecules that make up the pericellular matrix are likely to be the main cartilage components involved in cell-matrix interactions in the context of mechanotransduction.

Chondrocyte mechanoreceptor complexes

Mechanoreceptor complexes form and function in the plasma membrane, enabling chondrocytes to sense and respond to their mechanical environment [58, 68, 69]. Based on published information from a number of related and unrelated cell models we have recently proposed that chondrocyte mechanoreceptor complexes consist of β1-integrins associated with matrix macromolecules (i.e. collagen) serving as extracellular ligands for the receptor complex and signalling and cytoskeleton complexes responsible for intracellular communication.

Integrin receptors modulating cell–matrix interactions

Integrins are cell-surface receptors that mediate cell attachment to extracellular matrix components and act as molecular conduits for inside-out and outside-in signal transduction in focal adhesion sites [44]. Integrins are members of a multi-gene family with related structures and function. The β1 integrins (also known as CD29 or VLA, very late activation genes) are predominantly responsible for binding to the extracellular matrix [53]. The common feature of matrix binding integrins is β1 integrin [12] although the αsubunit may vary (see [36] for a recent review). Integrin-mediated adhesion to extracellular proteins can activate paxillin [4], tensin [1] and intracellular signalling proteins such as FAK (focal adhesion kinase) [46] (Fig. 4). In addition to their function as cell adhesion molecules in chondrocytes involved in cell-matrix interactions, cartilage remodelling and chondrogenesis [52, 53], integrins also play important roles as signalling receptors in chondrocytes [48]. Co-localization of β1 integrins (effectively chondrocyte-specific VLA-1, VLA-3 and VLA-5) with the insulin-like growth factor-I receptor (IGF-IR) suggests that matrix binding integrins and IGF-IR collaborate to regulate focal adhesion components in focal adhesion sites and their downstream functions including interactions with the cytoskeleton and mitogen-activated protein kinase signalling pathways [48]. Integrins also play a key role in sustaining the chondrocyte phenotype by maintaining a constant link with the extracellular matrix thus providing a critical survival signal.

Figure 4. Mechanoreceptor complex model.

Figure 4

Mechanoreceptor complex model. In this model integrins are attached to the extracellular ligand and the cytoskeleton complex. Integrin-mediated adhesion to extracellular proteins (i.e. collagen II, fibronectin, laminin, vitronectin) activates and recruits (more...)

Stretch-activated ion channels as mechanical signal transducers

The importance of the biophysical and electrophysiological aspects of the chondrocyte membrane has only recently been recognized, despite the fact that the cell membrane is the principal target for drugs and contains abundant receptors for hormones, growth factors and cytokines. A growing number of membrane transporters have been identified and characterized in chondrocytes and chondrocyte-like cells (for recent reviews see [34, 35, 36, 37]. The ions and their respective transport systems have already been proposed as putative mechanical signal transducers in articular cartilage [38]. Of the various transport systems studied in chondrocytes, four in particular have been investigated as potential mechanosensitive ion channels; voltage activated sodium and potassium channels [59, 68, 69], epithelial sodium channels (ENaC) [35, 61] and N-/L-type voltage activated calcium channels (VACC: [22, 67]). The rationale behind this concept is discussed in the following sections.

Changes in intracellular ion concentrations

In studies of mechanotransduction in chondrocytes and fibroblasts it has been demonstrated that Na+ ions first enter the cells, resulting in depolarisation of the membrane, which is followed by an elevation in intracellular Ca2+ causing hyperpolarization of the membrane. This opens Ca2+ activated K+ channels resulting in K+ efflux, in an effort to return the membrane potential to its original resting value (estimated at around -41 to -12 mV). This sequence of events requires voltage activated Na+, Ca2+ and K+ channels, all of which have been identified in chondrocytes [59]. We hypothesize that inward Na+ currents mediated by voltage activated sodium channels (VASC) and/or ENaC depolarise the chondrocyte membrane thus beginning a sequence of channel opening events (i.e. VACC, followed by Ca2+ activated K+ channels) elevating intracellular Ca2+ and culminating in the propagation of calcium waves that activate subcellular signalling cascades. Using fluorescent indicators to measure intracellular Ca2+ by fluorimetry or confocal microscopy in chondrocytes, it has been proposed that a transient increase in intracellular calcium [Ca2+]i is one of the earliest event in mechanical signal transduction [7, 8, 17, 22, 69]. This transient elevation in intracellular [Ca2+] is thought to occur following the depolarisation induced by Na+ influx and may be stimulated by deformation of the chondrocyte membrane, which initiates the generation of Ca2+ waves within chondrocytes [22]. Mechanosensitive ion channel blockers such as gadolinium (a broad and non-specific inhibitor of stretch-activated cation channels) and amiloride (inhibitor of epithelial sodium channels or ENaC and the Na+/H+ exchanger) inhibit these Ca2+ waves [22]. This functionally implicates both calcium and sodium channels in mechanotransduction [21, 22]. Voltage activated sodium channels have been shown to be functional in freshly isolated rabbit articular chondrocytes [59]. Voltage activated calcium channels have also been demonstrated in growth plate chondrocytes [71], articular chondrocytes [64] and mesenchymal chondroblast-like cells in developing limbs [49, 50].

Voltage-activated calcium channel activity

Electrophysiologically, N-type and L-type VACC have been demonstrated in chondrocytes [59, 67, 71]. The α1C-subunit of VACC has been shown to be expressed in osteoblasts and chondrocytes [67]. Since changes in intracellular Ca2+ are essential for calcium signalling following mechanical stimulation [22], VACC are believed to play a key role during mechanotransduction. In neuronal cells, calcium influx via VACC is controlled by cytoskeletal elements [13] and thus it may be possible that similar cytoskeletal regulatory mechanisms operate in other cell types including mechanosensitive chondrocytes.

Annexin V

The collagen binding protein annexin V has been found to exhibit calcium channel activity in addition to collagen binding. Annexin V is abundantly expressed in the plasma membrane of chondrocytes and has been shown to play a role in matrix vesicle-initiated cartilage calcification as a collagen-regulated calcium channel [66]. Annexin V represents another calcium entry pathway in chondrocytes that may be also involved in mechanotransduction.

Voltage-activated or epithelial sodium channel activity?

Although there is no molecular evidence for VASC expression in chondrocytes, studies by Wright with co-workers [68, 69] and Sugimoto with co-authors [59] have provided electrophysiological evidence for VASC activity in human, rat and rabbit articular chondrocytes. In rabbit chondrocytes, tetrodotoxin, a specific inhibitor of VASC completely blocks the inward Na+ current [59]. Thus, VASC is one ion channel candidate that may be responsible for the inward Na+ currents resulting in depolarisation of the chondrocyte membrane. Recent studies in our laboratories suggest that ENaC is also expressed in human chondrocytes [61], human chondrocyte-like cells [35] and mouse limb bud chondrocytes [49, 50]. Electrophysiological studies on isolated chondrocytes cells are currently in progress in our laboratory to help identify sodium currents activated in response to mechanical stimulation. Davidson and co-workers have demonstrated the existence of multiple forms of mechanosensitive non-selective cation channels in osteoblastic cells using the patch-clamp technique based on differences in their gating characteristics [10]. We have discussed the role of epithelial sodium channels (ENaC) in skeletal cell mechanotrannsduction elsewhere in this volume. Thus, evidence is emerging from a number of different musculoskeletal cell models including chondrocytes to functionally link the extracellular matrix and the subcellular cytoskeleton via plasma membrane resident integrin molecules in mechanosensory complexes. Indeed studies on renal epithelial cells have long demonstrated that ENaC is functionally linked to the actin cytoskeleton [5, 6, 56]. If ENaC and/or VASC were functionally linked to such mechanosensory complexes via integrins or linker proteins, they would perfectly fulfill the primary criteria for a stretch-activated mechanosensitive ion channels in chondrocytes. This would make chondrocytes unique in terms of the molecular machinery employed for the purposes of mechanotransduction.

Colocalization of β1-integrins with ENaC and VACC

Recent studies have shown that β1-integrins co-localize with Na, K-ATPase, epithelial sodium channels (ENaC) and voltage activated calcium channels (VACC) in mechanoreceptor complexes of mouse limb-bud chondrocytes [50]. It has been suggested that cellular responses and signalling cascades initiated by the influx of calcium or sodium through putative mechanosensitive channels may be regulated more effectively if such channels were organized around integrins with receptors, kinases and cytoskeletal complexes clustered about them. Since deformation induced Na+ and Ca2+ currents have been observed in chondrocytes and osteoblasts following stimulation by mechanical load [26, 59, 69], the expression and integrin colocalization of VACC and ENaC in chondrocytes makes them ideal candidates as mechanosensitive ion channels. Collaboration between β1-integrins, growth factor receptors, ion channels and ion transporters in chondrocytes may be a pre-requisite event preceding mechanotransduction.

Conclusions and perspectives

During growth and development, the skeletal system, particularly the cartilage lining the articulating surfaces of bones, optimizes its extracellular matrix architecture by subtle adaptations to the prevailing mechanical loads. The mechanisms for adaptation involve a multi-step process of cellular mechanotransduction including: mechano-coupling - conversion of mechanical forces into local mechanical signals, such as shear stresses, that initiate a response by chondrocytes; biochemical coupling - transduction of a mechanical signal to a biochemical response involving pathways within the cell membrane and cytoskeleton and finally modulation of gene expression and cell behaviour. Similar mechanisms operate in other related skeletal cell such as osteoblasts [62]. There is considerable evidence that ion channels residing in the plasma membrane of chondrocytes and osteoblasts are involved in the transduction of mechanical signals. Thus far, four candidate ion channels have been proposed to participate in chondrocytes; these include voltage activated potassium channels (VAKC), VASC, ENaC and VACC. Further details about the physiological and pharmacological properties of some of these channels may be found in one of our earlier reviews [34]. The precise sequence of events involved in the transduction process remains controversial. In light of our recent observations in mouse mesenchymal limb bud chondrocytes and the observations of other investigators working on freshly isolated chondrocytes from mature animals it is evident that the contribution of deformation of the pericellular matrix and the cellular cytoskeleton cannot be ignored [22, 30]. The mechanisms of intracellular signalling involved in mechanotransduction seem to involve traditional messenger molecules such as Ca2+, IP3 and cAMP as well as novel pathways involving the pericellular matrix, the chondrocyte membrane, the intracellular cytoskeleton and the nucleus [21]. Although the composition of the mechanosensory complexes proposed here may be unique chondrocytes and osteoblasts, the intracellular participants, intracellular signalling pathways (i.e. MAP kinases) and second messengers (i.e. Ca2+, IP3 and cAMP) appear to be common to many other cell types.

Chondrocytes within articular cartilage express a variety of integrins and mechanosensitive ion channels. The molecular composition of the chondrocyte mechanoreceptor complex is still not known. However, given the involvement of integrins, ion channels and the cellular cytoskeleton in mechanical signal transduction in other systems [6, 24], it is likely that these molecules colocalize and collaborate in mechanoreceptor complexes in chondrocytes. Co-localization of ENaC and VACC with integrins makes them ideal candidates in the mechanotransduction pathway (see proposed model in Figure 5). Further work is required to determine the functional significance of these novel interactions. The use of antisense technology or transgenic mouse models, ion channel modulators (i.e. specific blockers and openers) combined with drugs capable of disrupting distinct components of the cytoskeleton in well-defined experimental procedures where chondrocyte integrins are functionally activated will shed further light on these intricate transduction mechanisms.

Figure 5. Proposed model of integrins and the focal adhesion complex incorporating putative mechanosensitive ion channels.

Figure 5

Proposed model of integrins and the focal adhesion complex incorporating putative mechanosensitive ion channels. This model of the chondrocyte mechanoreceptor complex incorporates the extracellular ligand conveying the mechanical signal, integrins, putative (more...)

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