Mechanotransduction

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See also: Mechanosensation

In

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
.

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

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

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
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

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

One of the main mechanical functions of articular

chondrocytes
(cartilage cells).

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

growth factors.[20][21]

The balance that is struck between

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

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.

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,

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

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]

References

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Further reading

External links
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