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. Current findings indicate that the mechanotransduction channel in hair cells complex biological machine. Mechanotransduction also includes the use of chemical energy to do mechanical work. [12]

Cellular mechanotransduction

Cells continuously detect and respond to mechanical cues in their individual environments: substrate stiffness, shear stress, tension, and compression. These forces are converted into biochemical signals through mechanotransduction pathways, allowing cells to regulate their behavior: migration, death, structural changes, gene expression, and cell differentiation. [13]

General cellular mechanotransduction pathway

The following are the typical steps of a mechanotransduction pathway: [13]

  1. A mechanical force is applied (tension, rigidity, friction, sheer force, etc).
  2. A force-sensitive protein (often mechanosensitive channels) responds to the mechanical force.
  3. An electrochemical gradient or change in cell polarity is produced directly or indirectly by the force-sensitive protein.
  4. This gradient or polarity produces an effect or output that changes cell behavior.

Mechanical sensing structures

Cells use the following structures in specialized ways to detect mechanical forces.

Mechanical forces applied to these structures can activate intracellular signaling pathways, alter cytoskeletal tension, and change gene transcription (see linked sources for specific pathways).

Examples of these mechanical sensing structures leading to mechanotransduced behavior changes are listed below.

Cellular Mechanotransduction Pathway Examples
Mechanical CueCellular SensorCommon Cellular Resposne(s)
Substrate stiffnessIntegrins, cytoskeleton, nucleusDifferentiation [13] , apoptosis [15] , migration [13]
Shear stressIon channels, glycocalyx Endothelial alignment [16]
CompressionCytoskeleton, nucleusGene regulation [15]
TensionIntegrins, cytockeletonStress fiber formation, contractility

Aberrant cellular mechanotransduction

Unusual or altered mechanotransduction has been correlated with changes in cell behavior. As well, changes to the medium on which cells grow (the extracellular matrix) can often regulate cell activity through to mechanotransduction. Thus, these changes to the extracellular matrix can result in unhealthy cell activity.

Cancer

Cell behavior changes resulting from aberrant mechanotransduction may lead to cancer. Substrate stiffness (more abundant around cancerous tissue) can be transduced into signaling pathways that lead to cell death or migration. [13] [15] Apoptosis can be regulated by the stiffness of the extracellular matrix. [15] Rigidity-sensing complexes regulating where cells grow or travel is partially managed by mechanotransduction. [17] Alterations to this rigidity-sensing mechanotransduction can promote cancer: loss in rigidity-sensing complexes can, for example, lead to growth on soft tissue without apoptosis. [18]

Cross-linked extracellular matrix proteins in tumors leads to stiffness that has been shown to favor cancer development. [19] Through mechano-sensitive pathways, this stiffness can lead to metastasis through the stimulation of epithelial-mesenchymal transition (EMT) [20] which is associated with anoikis avoidance - stimulating cell migration.

Fibrosis

Mechanotransduction pathways, such as FAK-ERK, have been shown to be involved in fibrosis. [21]

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. [22] 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. [23]

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. [24]

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, 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. [25] [26]

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. [27] [28] Decreased mechanical loading over long periods, such as during extended bed-rest, causes a loss of matrix production. [29] Static loads have been shown to be detrimental to biosynthesis [30] 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. [31] 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), [32] the hyaluronan receptor CD44, annexin V (a collagen type II receptor), [33] 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, [34] mediate survival signaling [35] and regulate matrix production and degradation. [36]

Integrin receptors have an extracellular domain that binds to the extracellular matrix proteins (collagen, fibronectin, laminin, vitronectin and osteopontin), and a cytoplasmic domain that interacts with intracellular signaling molecules. When an integrin receptor binds to its extracellular matrix ligand and is activated, additional integrins cluster around the activated site. In addition, kinases (e.g., focal adhesion kinase and adapter proteins (e.g., paxillin, aka Pax, talin, aka Tal, and Shc) are recruited to this cluster, which is called the focal adhesion complex. The activation of these focal adhesion complex 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 extracellular matrix 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. [37]

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 [38] as well as changes in cAMP levels, actin re-organization and changes in the expression of genes which regulate cartilage extracellular matrix content. [39]

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 extracellular matrix loading. Integrins have been identified on the upper shaft of the cilium, acting as anchors to the collagen matrix around it. [40] 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 [41]

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 ]

References

  1. ↑ Biswas, Abhijit; Manivannan, M.; Srinivasan, Mandyam A. (2015). "Vibrotactile Sensitivity Threshold: Nonlinear Stochastic Mechanotransduction Model of the Pacinian Corpuscle". IEEE Transactions on Haptics. 8 (1): 102–113. doi:10.1109/TOH.2014.2369422. PMID   25398183. S2CID   15326972.
  2. ↑ Katsumi, A.; Orr, AW; Tzima, E; Schwartz, MA (2003). "Integrins in Mechanotransduction". Journal of Biological Chemistry. 279 (13): 12001–4. doi: 10.1074/jbc.R300038200 . PMID   14960578.
  3. ↑ Qin, Y.; Qin, Y; Liu, J; Tanswell, AK; Post, M (1996). "Mechanical Strain Induces pp60src Activation and Translocation to Cytoskeleton in Fetal Rat Lung Cells". Journal of Biological Chemistry. 271 (12): 7066–71. doi: 10.1074/jbc.271.12.7066 . PMID   8636139.
  4. ↑ Bidhendi, Amir J; Altartouri, Bara; Gosselin, Frédérick P.; Geitmann, Anja (2019). "Mechanical stress initiates and sustains the morphogenesis of wavy leaf epidermal cells". Cell Reports. 28 (5): 1237–1250. doi: 10.1016/j.celrep.2019.07.006 . PMID   31365867.
  5. ↑ Biswas, Abhijit; Manivannan, M.; Srinivasan, Mandyam A. (2014). "Nonlinear two stage mechanotransduction model and neural response of Pacinian Corpuscle". Biomedical Science and Engineering Center Conference (BSEC), 2014 Annual Oak Ridge National Laboratory. USA: IEEE. pp. 1–4. doi:10.1109/BSEC.2014.6867740.
  6. ↑ Tavernarakis, Nektarios; Driscoll, Monica (1997). "Molecular Modeling of Mechanotransduction in the Nematode Caenorhabditis Elegans". Annual Review of Physiology. 59: 659–89. doi:10.1146/annurev.physiol.59.1.659. PMID   9074782.
  7. ↑ Howard, J; Roberts, W M; Hudspeth, A J (1988). "Mechanoelectrical Transduction by Hair Cells". Annual Review of Biophysics and Biophysical Chemistry. 17: 99–124. doi:10.1146/annurev.bb.17.060188.000531. PMID   3293600.
  8. ↑ Hackney, CM; Furness, DN (1995). "Mechanotransduction in vertebrate hair cells: Structure and function of the stereociliary bundle". The American Journal of Physiology. 268 (1 Pt 1): C1–13. doi:10.1152/ajpcell.1995.268.1.C1. PMID   7840137.
  9. ↑ Gillespie, Peter G.; Walker, Richard G. (2001). "Molecular basis of mechanosensory transduction". Nature. 413 (6852): 194–202. Bibcode:2001Natur.413..194G. doi:10.1038/35093011. PMID   11557988. S2CID   4388399.
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  11. ↑ Biswas, Abhijit; Manivannan, M.; Srinivasan, Mandyam A. (2015). "Multiscale Layered Biomechanical Model of the Pacinian Corpuscle". IEEE Transactions on Haptics. 8 (1): 31–42. doi:10.1109/TOH.2014.2369416. PMID   25398182. S2CID   24658742.
  12. ↑ {{cite book|last1=Nakano|first1=Tadashi|last2=Eckford|first2=Andrew W.|last3=Haraguchi|first3=Tokuko|title=Molecular Communication|url=https://books.google.com/books?id=uVhsAAAAQBAJ|date=12 September 2013|publisher=Cambridge University Press|isbn=978-1-107-02308-6}}
  13. 1 2 3 4 5 6 7 Wolfenson, Haguy; Yang, Bo; Sheetz, Michael P. (2019-02-10). "Steps in Mechanotransduction Pathways that Control Cell Morphology". Annual Review of Physiology. 81: 585–605. doi:10.1146/annurev-physiol-021317-121245. ISSN   1545-1585. PMC   7476682 . PMID   30403543.
  14. ↑ Roeterink, Renate M. A.; Casadevall I Solvas, Xevi; Collins, David J.; Scott, Daniel J. (December 2024). "Force versus Response: Methods for Activating and Characterizing Mechanosensitive Ion Channels and GPCRs". Advanced Healthcare Materials. 13 (31) e2402167. doi:10.1002/adhm.202402167. ISSN   2192-2659. PMC   11650423 . PMID   39402780.
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  16. ↑ Power, Gavin; Ferreira-Santos, Larissa; Martinez-Lemus, Luis A.; Padilla, Jaume (2024-10-01). "Integrating molecular and cellular components of endothelial shear stress mechanotransduction". American Journal of Physiology. Heart and Circulatory Physiology. 327 (4): H989 –H1003. doi:10.1152/ajpheart.00431.2024. ISSN   1522-1539. PMC   11482243 . PMID   39178024.
  17. ↑ Meacci, Giovanni; Wolfenson, Haguy; Liu, Shuaimin; Stachowiak, Matthew R.; Iskratsch, Thomas; Mathur, Anurag; Ghassemi, Saba; Gauthier, Nils; Tabdanov, Erdem; Lohner, James; Gondarenko, Alexander; Chander, Ashok C.; Roca-Cusachs, Pere; O'Shaughnessy, Ben; Hone, James (2016-11-07). "α-Actinin links extracellular matrix rigidity-sensing contractile units with periodic cell-edge retractions". Molecular Biology of the Cell. 27 (22): 3471–3479. doi:10.1091/mbc.E16-02-0107. ISSN   1939-4586. PMC   5221581 . PMID   27122603.
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  19. ↑ Paszek, Matthew J.; Zahir, Nastaran; Johnson, Kandice R.; Lakins, Johnathon N.; Rozenberg, Gabriela I.; Gefen, Amit; Reinhart-King, Cynthia A.; Margulies, Susan S.; Dembo, Micah; Boettiger, David; Hammer, Daniel A.; Weaver, Valerie M. (2005-09-01). "Tensional homeostasis and the malignant phenotype". Cancer Cell. 8 (3): 241–254. doi:10.1016/j.ccr.2005.08.010. ISSN   1535-6108.
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  21. ↑ Lagares, David; Busnadiego, Oscar; García-Fernández, Rosa Ana; Kapoor, Mohit; Liu, Shangxi; Carter, David E.; Abraham, David; Shi-Wen, Xu; Carreira, Patricia; Fontaine, Benjamin A.; Shea, Barry S.; Tager, Andrew M.; Leask, Andrew; Lamas, Santiago; Rodríguez-Pascual, Fernando (May 2012). "Inhibition of focal adhesion kinase prevents experimental lung fibrosis and myofibroblast formation". Arthritis and Rheumatism. 64 (5): 1653–1664. doi:10.1002/art.33482. ISSN   1529-0131. PMC   3338902 . PMID   22492165.
  22. ↑ Ehret, Günter (2009-05-08). "Stiffness gradient along the basilar membrane as a basis for spatial frequency analysis within the cochlea". doi:10.18725/OPARU-1218.{{cite journal}}: Cite journal requires |journal= (help)
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  26. ↑ Fitzgerald, J. B.; Jin, M; Grodzinsky, AJ (2006). "Shear and Compression Differentially Regulate Clusters of Functionally Related Temporal Transcription Patterns in Cartilage Tissue". Journal of Biological Chemistry. 281 (34): 24095–103. doi: 10.1074/jbc.M510858200 . PMID   16782710.
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  29. ↑ Behrens, Fred; Kraft, Ellen L.; Oegema, Theodore R. (1989). "Biochemical changes in articular cartilage after joint immobilization by casting or external fixation". Journal of Orthopaedic Research. 7 (3): 335–43. doi:10.1002/jor.1100070305. PMID   2703926. S2CID   34651862.
  30. ↑ Torzilli, P. A.; Deng, X-H.; Ramcharan, M. (2006). "Effect of Compressive Strain on Cell Viability in Statically Loaded Articular Cartilage". Biomechanics and Modeling in Mechanobiology. 5 (2–3): 123–32. doi:10.1007/s10237-006-0030-5. PMID   16506016. S2CID   39216430.
  31. ↑ Sah, Robert L.-Y.; Kim, Young-Jo; Doong, Joe-Yuan H.; Grodzinsky, Alan J.; Plass, Anna H. K.; Sandy, John D. (1989). "Biosynthetic response of cartilage explants to dynamic compression". Journal of Orthopaedic Research. 7 (5): 619–36. doi:10.1002/jor.1100070502. PMID   2760736. S2CID   1933220.
  32. ↑ Mouw, J. K.; Imler, S. M.; Levenston, M. E. (2006). "Ion-channel Regulation of Chondrocyte Matrix Synthesis in 3D Culture Under Static and Dynamic Compression". Biomechanics and Modeling in Mechanobiology. 6 (1–2): 33–41. doi:10.1007/s10237-006-0034-1. PMID   16767453. S2CID   7270995.
  33. ↑ Von Der Mark, K.; Mollenhauer, J. (1997). "Annexin V interactions with collagen". Cellular and Molecular Life Sciences. 53 (6): 539–45. doi:10.1007/s000180050069. PMC   11147192 . PMID   9230933. S2CID   21313045.
  34. ↑ Kurtis, Melissa S.; Tu, Buu P.; Gaya, Omar A.; Mollenhauer, Jürgen; Knudson, Warren; Loeser, Richard F.; Knudson, Cheryl B.; Sah, Robert L. (2001). "Mechanisms of chondrocyte adhesion to cartilage: Role of β1-integrins, CD44, and annexin V". Journal of Orthopaedic Research. 19 (6): 1122–30. doi: 10.1016/S0736-0266(01)00051-1 . PMID   11781014.
  35. ↑ Pulai, Judit I.; Del Carlo, Marcello; Loeser, Richard F. (2002). "The ?5?1 integrin provides matrix survival signals for normal and osteoarthritic human articular chondrocytes in vitro". Arthritis & Rheumatism. 46 (6): 1528–35. doi: 10.1002/art.10334 . PMID   12115183.
  36. ↑ Millward–Sadler, S. J.; Wright, M. O.; Davies, L. W.; Nuki, G.; Salter, D. M. (2000). "Mechanotransduction via integrins and interleukin–4 results in altered aggrecan and matrix metalloproteinase 3 gene expression in normal, but not osteoarthritic, human articular chondrocytes". Arthritis & Rheumatism. 43 (9): 2091–2099. doi: 10.1002/1529-0131(200009)43:9<2091::AID-ANR21>3.0.CO;2-C . PMID   11014361.
  37. ↑ Millward-Sadler, S. J.; Salter, D. M. (2004). "Integrin-Dependent Signal Cascades in Chondrocyte Mechanotransduction". Annals of Biomedical Engineering. 32 (3): 435–46. doi:10.1023/B:ABME.0000017538.72511.48. PMID   15095818. S2CID   1717838.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ 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.
  41. ↑ 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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