Mechanotransduction

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In cellular biology, mechanotransduction ( mechano + transduction ) is any of various mechanisms by which cells convert mechanical stimulus into electrochemical activity. [1] [2] [3] [4] This form of sensory transduction is responsible for a number of senses and physiological processes in the body, including proprioception, touch, [5] balance, and hearing. [6] [7] [8] The basic mechanism of mechanotransduction involves converting mechanical signals into electrical or chemical signals.

Contents

Some biological machines Molecular Machines of Life.jpg
Some biological machines

In this process, a mechanically gated ion channel makes it possible for sound, pressure, or movement to cause a change in the excitability of specialized sensory cells and sensory neurons. [9] The stimulation of a mechanoreceptor causes mechanically sensitive ion channels to open and produce a transduction current that changes the membrane potential of the cell. [10] Typically the mechanical stimulus gets filtered in the conveying medium before reaching the site of mechanotransduction. [11] Cellular responses to mechanotransduction are variable and give rise to a variety of changes and sensations. Broader issues involved include molecular biomechanics.

Single-molecule biomechanics studies of proteins and DNA, and mechanochemical coupling in molecular motors have demonstrated the critical importance of molecular mechanics as a new frontier in bioengineering and life sciences. Protein domains, connected by intrinsically disordered flexible linker domains, induce long-range allostery via protein domain dynamics. The resultant dynamic modes cannot be generally predicted from static structures of either the entire protein or individual domains. They can however be inferred by comparing different structures of a protein (as in Database of Molecular Motions). They can also be suggested by sampling in extensive molecular dynamics trajectories [12] and principal component analysis, [13] or they can be directly observed using spectra [14] [15] measured by neutron spin echo spectroscopy. Current findings indicate that the mechanotransduction channel in hair cells is a complex biological machine. Mechanotransduction also includes the use of chemical energy to do mechanical work. [16]

Ear

Air pressure changes in the ear canal cause the vibrations of the tympanic membrane and middle ear ossicles. At the end of the ossicular chain, movement of the stapes footplate within the oval window of the cochlea generates a pressure field within the cochlear fluids, imparting a pressure differential across the basilar membrane. A sinusoidal pressure wave results in localized vibrations of the organ of Corti: near the base for high frequencies, near the apex for low frequencies. [17] Hair cells in the cochlea are stimulated when the basilar membrane is driven up and down by differences in the fluid pressure between the scala vestibuli and scala tympani. This motion is accompanied by a shearing motion between the tectorial membrane and the reticular lamina of the organ of Corti, causing the hair bundles that link the two to be deflected, initiating mechano-electrical transduction. When the basilar membrane is driven upward, shear between the hair cells and the tectorial membrane deflects hair bundles in the excitatory direction, toward their tall edge. At the midpoint of an oscillation the hair bundles resume their resting position. When the basilar membrane moves downward, the hair bundles are driven in the inhibitory direction. [18]

Skeletal muscle

When a deformation is imposed on a muscle, changes in cellular and molecular conformations link the mechanical forces with biochemical signals, and the close integration of mechanical signals with electrical, metabolic, and hormonal signaling may disguise the aspect of the response that is specific to the mechanical forces. [19]

Cartilage

Mechanically gated channel Mechanically Gated Channel.png
Mechanically gated channel

One of the main mechanical functions of articular cartilage is to act as a low-friction, load-bearing surface. Due to its unique location at joint surfaces, articular cartilage experiences a range of static and dynamic forces that include shear, compression and tension. These mechanical loads are absorbed by the cartilage extracellular matrix (ECM), where they are subsequently dissipated and transmitted to chondrocytes (cartilage cells).

Cartilage experience tension, compression and shear forces in vivo Cartilage forces.jpg
Cartilage experience tension, compression and shear forces in vivo

Chondrocytes sense and convert the mechanical signals they receive into biochemical signals, which subsequently direct and mediate both anabolic (matrix building) and catabolic (matrix degrading) processes. These processes include the synthesis of matrix proteins (type II collagen and proteoglycans), proteases, protease inhibitors, transcription factors, cytokines and growth factors. [20] [21]

The balance that is struck between anabolic and catabolic processes is strongly influenced by the type of loading that cartilage experiences. High strain rates (such as which occurs during impact loading) cause tissue damage, degradation, decreased matrix production and apoptosis. [22] [23] Decreased mechanical loading over long periods, such as during extended bed-rest, causes a loss of matrix production. [24] Static loads have been shown to be detrimental to biosynthesis [25] while oscillatory loads at low frequencies (similar that of a normal walking gait) have been shown to be beneficial in maintaining health and increasing matrix synthesis. [26] Due to the complexity of in-vivo loading conditions and the interplay of other mechanical and biochemical factors, the question of what an optimal loading regimen may be or whether one exists remain unanswered.

Although studies have shown that, like most biological tissues, cartilage is capable of mechanotransduction, the precise mechanisms by which this is done remain unknown. However, there exist a few hypotheses which begin with the identification of mechanoreceptors.[ citation needed ]

In order for mechanical signals to be sensed, there need to be mechanoreceptors on the surface of chondrocytes. Candidates for chondrocyte mechanoreceptors include stretch-activated ion channels (SAC), [27] the hyaluronan receptor CD44, annexin V (a collagen type II receptor), [28] and integrin receptors (of which there exist several types on chondrocytes).

Chondrocyte surface mechano-receptors include CD44, annexin V and integrins. Chondrocyte extracellular matrix components include collagens, proteoglycans (which consist of aggrecan and hyaluronan), fibronectin and COMP. Chondrocyte receptors.jpg
Chondrocyte surface mechano-receptors include CD44, annexin V and integrins. Chondrocyte extracellular matrix components include collagens, proteoglycans (which consist of aggrecan and hyaluronan), fibronectin and COMP.

Using the integrin-linked mechanotransduction pathway as an example (being one of the better studied pathways), it has been shown to mediate chondrocyte adhesion to cartilage surfaces, [29] mediate survival signaling [30] and regulate matrix production and degradation. [31]

Integrin receptors have an extracellular domain that binds to the ECM proteins (collagen, fibronectin, laminin, vitronectin and osteopontin), and a cytoplasmic domain that interacts with intracellular signaling molecules. When an integrin receptor binds to its ECM ligand and is activated, additional integrins cluster around the activated site. In addition, kinases (e.g., focal adhesion kinase, FAK) and adapter proteins (e.g., paxillin, Pax, talin, Tal and Shc) are recruited to this cluster, which is called the focal adhesion complex (FAC). The activation of these FAC molecules in turn, triggers downstream events that up-regulate and /or down-regulate intracellular processes such as transcription factor activation and gene regulation resulting in apoptosis or differentiation.[ citation needed ]

In addition to binding to ECM ligands, integrins are also receptive to autocrine and paracrine signals such as growth factors in the TGF-beta family. Chondrocytes have been shown to secrete TGF-b, and upregulate TGF-b receptors in response to mechanical stimulation; this secretion may be a mechanism for autocrine signal amplification within the tissue. [32]

Integrin signaling is just one example of multiple pathways that are activated when cartilage is loaded. Some intracellular processes that have been observed to occur within these pathways include phosphorylation of ERK1/2, p38 MAPK, and SAPK/ERK kinase-1 (SEK-1) of the JNK pathway [33] as well as changes in cAMP levels, actin re-organization and changes in the expression of genes which regulate cartilage ECM content. [34]

More recent studies have hypothesized that chondrocyte primary cilium act as a mechanoreceptor for the cell, transducing forces from the extracellular matrix into the cell. Each chondrocyte has one cilium and it is hypothesized to transmit mechanical signals by way of bending in response to ECM loading. Integrins have been identified on the upper shaft of the cilium, acting as anchors to the collagen matrix around it. [35] Recent studies published by Wann et al. in FASEB Journal have demonstrated for the first time that primary cilia are required for chondrocyte mechanotransduction. Chondrocytes derived from IFT88 mutant mice did not express primary cilia and did not show the characteristic mechanosensitive up regulation of proteoglycan synthesis seen in wild type cells [36]

It is important to examine the mechanotransduction pathways in chondrocytes since mechanical loading conditions which represent an excessive or injurious response upregulates synthetic activity and increases catabolic signalling cascades involving mediators such as NO and MMPs. In addition, studies by Chowdhury TT and Agarwal S have shown that mechanical loading which represents physiological loading conditions will block the production of catabolic mediators (iNOS, COX-2, NO, PGE2) induced by inflammatory cytokines (IL-1) and restore anabolic activities. Thus an improved understanding of the interplay of biomechanics and cell signalling will help to develop therapeutic methods for blocking catabolic components of the mechanotransduction pathway. A better understanding of the optimal levels of in vivo mechanical forces are therefore necessary for maintaining the health and viability of cartilage, preventative techniques may be devised for the prevention of cartilage degradation and disease.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Integrin</span> Instance of a defined set in Homo sapiens with Reactome ID (R-HSA-374573)

Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, organization of the intracellular cytoskeleton, and movement of new receptors to the cell membrane. The presence of integrins allows rapid and flexible responses to events at the cell surface.

<span class="mw-page-title-main">Signal transduction</span> Cascade of intracellular and molecular events for transmission/amplification of signals

Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding in a receptor give rise to a biochemical cascade, which is a chain of biochemical events known as a signaling pathway.

<span class="mw-page-title-main">Cartilage</span> Resilient and smooth elastic tissue in animals

Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck and the bronchial tubes, and the intervertebral discs. In other taxa, such as chondrichthyans, but also in cyclostomes, it may constitute a much greater proportion of the skeleton. It is not as hard and rigid as bone, but it is much stiffer and much less flexible than muscle. The matrix of cartilage is made up of glycosaminoglycans, proteoglycans, collagen fibers and, sometimes, elastin.

<span class="mw-page-title-main">Extracellular matrix</span> Network of proteins and molecules outside cells that provides structural support for cells

In biology, the extracellular matrix (ECM) is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and biochemical support to surrounding cells. Because multicellularity evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-to-cell communication and differentiation are common functions of the ECM.

<span class="mw-page-title-main">Organ of Corti</span> Receptor organ for hearing

The organ of Corti, or spiral organ, is the receptor organ for hearing and is located in the mammalian cochlea. This highly varied strip of epithelial cells allows for transduction of auditory signals into nerve impulses' action potential. Transduction occurs through vibrations of structures in the inner ear causing displacement of cochlear fluid and movement of hair cells at the organ of Corti to produce electrochemical signals.

In physiology, transduction is the translation of arriving stimulus into an action potential by a sensory receptor. It begins when stimulus changes the membrane potential of a receptor cell.

<span class="mw-page-title-main">Hair cell</span> Auditory sensory receptor nerve cells

Hair cells are the sensory receptors of both the auditory system and the vestibular system in the ears of all vertebrates, and in the lateral line organ of fishes. Through mechanotransduction, hair cells detect movement in their environment.

Durotaxis is a form of cell migration in which cells are guided by rigidity gradients, which arise from differential structural properties of the extracellular matrix (ECM). Most normal cells migrate up rigidity gradients.

<span class="mw-page-title-main">Chondrocyte</span> Cell that makes up cartilage

Chondrocytes are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word chondroblast is commonly used to describe an immature chondrocyte, the term is imprecise, since the progenitor of chondrocytes can differentiate into various cell types, including osteoblasts.

<span class="mw-page-title-main">Chondroblast</span> Mesenchymal progenitor cell that forms a chondrocyte

Chondroblasts, or perichondrial cells, is the name given to mesenchymal progenitor cells in situ which, from endochondral ossification, will form chondrocytes in the growing cartilage matrix. Another name for them is subchondral cortico-spongious progenitors. They have euchromatic nuclei and stain by basic dyes.

<span class="mw-page-title-main">Chondrogenesis</span> Process by which cartilage is developed

Chondrogenesis is the process by which cartilage is developed.

Articular cartilage, most notably that which is found in the knee joint, is generally characterized by very low friction, high wear resistance, and poor regenerative qualities. It is responsible for much of the compressive resistance and load bearing qualities of the knee joint and, without it, walking is painful to impossible. Osteoarthritis is a common condition of cartilage failure that can lead to limited range of motion, bone damage and invariably, pain. Due to a combination of acute stress and chronic fatigue, osteoarthritis directly manifests itself in a wearing away of the articular surface and, in extreme cases, bone can be exposed in the joint. Some additional examples of cartilage failure mechanisms include cellular matrix linkage rupture, chondrocyte protein synthesis inhibition, and chondrocyte apoptosis. There are several different repair options available for cartilage damage or failure.

<span class="mw-page-title-main">Aggrecan</span>

Aggrecan (ACAN), also known as cartilage-specific proteoglycan core protein (CSPCP) or chondroitin sulfate proteoglycan 1, is a protein that in humans is encoded by the ACAN gene. This gene is a member of the lectican family. The encoded protein is an integral part of the extracellular matrix in cartilagenous tissue and it withstands compression in cartilage.

<span class="mw-page-title-main">Integrin beta 1</span>

Integrin beta-1 (ITGB1), also known as CD29, is a cell surface receptor that in humans is encoded by the ITGB1 gene. This integrin associates with integrin alpha 1 and integrin alpha 2 to form integrin complexes which function as collagen receptors. It also forms dimers with integrin alpha 3 to form integrin receptors for netrin 1 and reelin. These and other integrin beta 1 complexes have been historically known as very late activation (VLA) antigens.

Mechanosensation is the transduction of mechanical stimuli into neural signals. Mechanosensation provides the basis for the senses of light touch, hearing, proprioception, and pain. Mechanoreceptors found in the skin, called cutaneous mechanoreceptors, are responsible for the sense of touch. Tiny cells in the inner ear, called hair cells, are responsible for hearing and balance. States of neuropathic pain, such as hyperalgesia and allodynia, are also directly related to mechanosensation. A wide array of elements are involved in the process of mechanosensation, many of which are still not fully understood.

Mechanosensitive channels, mechanosensitive ion channels or stretch-gated ion channels (not to be confused with mechanoreceptors). They are present in the membranes of organisms from the three domains of life: bacteria, archaea, and eukarya. They are the sensors for a number of systems including the senses of touch, hearing and balance, as well as participating in cardiovascular regulation and osmotic homeostasis (e.g. thirst). The channels vary in selectivity for the permeating ions from nonselective between anions and cations in bacteria, to cation selective allowing passage Ca2+, K+ and Na+ in eukaryotes, and highly selective K+ channels in bacteria and eukaryotes.

Mechanobiology is an emerging field of science at the interface of biology, engineering, chemistry and physics. It focuses on how physical forces and changes in the mechanical properties of cells and tissues contribute to development, cell differentiation, physiology, and disease. Mechanical forces are experienced and may be interpreted to give biological responses in cells. The movement of joints, compressive loads on the cartilage and bone during exercise, and shear pressure on the blood vessel during blood circulation are all examples of mechanical forces in human tissues. A major challenge in the field is understanding mechanotransduction—the molecular mechanisms by which cells sense and respond to mechanical signals. While medicine has typically looked for the genetic and biochemical basis of disease, advances in mechanobiology suggest that changes in cell mechanics, extracellular matrix structure, or mechanotransduction may contribute to the development of many diseases, including atherosclerosis, fibrosis, asthma, osteoporosis, heart failure, and cancer. There is also a strong mechanical basis for many generalized medical disabilities, such as lower back pain, foot and postural injury, deformity, and irritable bowel syndrome.

Gene therapy is being studied as a treatment for osteoarthritis (OA). Unlike pharmacological treatments which are administered systemically, gene therapy aims to establish sustained, synthesis of gene products and tissue rehabilitation within the joint.

<span class="mw-page-title-main">Integrin-like receptors</span>

Integrin-like receptors (ILRs) are found in plants and carry unique functional properties similar to true integrin proteins. True homologs of integrins exist in mammals, invertebrates, and some fungi but not in plant cells. Mammalian integrins are heterodimer transmembrane proteins that play a large role bidirectional signal transduction. As transmembrane proteins, integrins connect the extracellular matrix (ECM) to the plasma membrane of the animal cell. The extracellular matrix of plant cells, fungi, and some protist is referred to as the cell wall. The plant cell wall is composed of a tough cellulose polysaccharide rather than the collagen fibers of the animal ECM. Even with these differences, research indicates that similar proteins involved in the interaction between the ECM and animals cells are also involved in the interaction of the cell wall and plant cells.

Artificial cartilage is a synthetic material made of hydrogels or polymers that aims to mimic the functional properties of natural cartilage in the human body. Tissue engineering principles are used in order to create a non-degradable and biocompatible material that can replace cartilage. While creating a useful synthetic cartilage material, certain challenges need to be overcome. First, cartilage is an avascular structure in the body and therefore does not repair itself. This creates issues in regeneration of the tissue. Synthetic cartilage also needs to be stably attached to its underlying surface, bone. Lastly, in the case of creating synthetic cartilage to be used in joint spaces, high mechanical strength under compression needs to be an intrinsic property of the material.

References

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  33. ↑ Fanning, P. J.; Emkey, G; Smith, RJ; Grodzinsky, AJ; Szasz, N; Trippel, SB (2003). "Mechanical Regulation of Mitogen-activated Protein Kinase Signaling in Articular Cartilage". Journal of Biological Chemistry. 278 (51): 50940–8. doi: 10.1074/jbc.M305107200 . PMID   12952976.
  34. ↑ Urban, J. P. G. (1994). "The Chondrocyte: A Cell Under Pressure". Rheumatology. 33 (10): 901–908. doi:10.1093/rheumatology/33.10.901. PMID   7921748.
  35. ↑ McGlashan, S. R.; Jensen, CG; Poole, CA (2006). "Localization of Extracellular Matrix Receptors on the Chondrocyte Primary Cilium". Journal of Histochemistry and Cytochemistry. 54 (9): 1005–14. doi: 10.1369/jhc.5A6866.2006 . PMID   16651393.
  36. ↑ Wann, AK; Zuo, N; Haycraft, CJ; et al. (April 2012). "Primary cilia mediate mechanotransduction through control of ATP-induced Ca2+ signaling in compressed chondrocytes". FASEB J. 26 (4): 1663–71. doi:10.1096/fj.11-193649. PMC   3316893 . PMID   22223751.

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