Mechanotransduction
Encyclopedia
Mechanotransduction refers to the many mechanism
s by which cells convert mechanical stimulus
into chemical activity.
s of the cochlea
in the inner 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, in turn, 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. The cochlea thus acts as an “acoustic prism”, distributing the energy of each Fourier
component of a complex sound at different locations along its longitudinal axis. 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
. Because this motion is accompanied by a shearing motion between the tectorial membrane
and the reticular lamina of the organ of Corti, the hair bundles that link the two are deflected, which initiates 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.
Basilar Membrane motion causes a shearing motion between the reticular lamina and the tectorial membrane, thereby activating the mechano-sensory apparatus of the hair bundle, which in turn generates a receptor potential
in the hair cells.
Thus the sound pressure wave is transduced to an electrical signal which can be processed as sound in higher parts of the auditory system
.
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).
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.,
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
., Decreased mechanical loading over long periods, such as during extended bed-rest, causes a loss of matrix production. Static loads have been shown to be detrimental to biosynthesis 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. 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.
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 channel
s (SAC), the hyaluronan receptor CD44
, annexin V (a collagen type II receptor), and integrin
receptors (of which there exist several types on chondrocytes).
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, mediate survival signaling and regulate matrix production and degradation.
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.
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.
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 as well as changes in cAMP levels, actin re-organization and changes in the expression of genes which regulate cartilage ECM content.
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 (α2β1 and α3β1 ) have been identified on the upper shaft of the cilium, acting as anchors to the collagen matrix around it. However, in spite of results from recent studies (such as those from the lab of C.A. Poole) the mechanotransduction role of cilia remains to be proven.
It is important to examine the mechanotransduction pathways in chondrocytes since mechanical loading conditions which represent an excessive or injuruous 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.
Mechanism (biology)
In biology --and in science in general-- a mechanism is a complex object or, more generally, a process that produces a regular phenomenon. For example, natural selection is one of the mechanisms of biological evolution, other being genetic drift, biased mutation, and gene flow; competition,...
s by which cells convert mechanical stimulus
Wolff's law
Wolff's law is a theory developed by the German Anatomist/Surgeon Julius Wolff in the 19th century that states that bone in a healthy person or animal will adapt to the loads it is placed under. If loading on a particular bone increases, the bone will remodel itself over time to become stronger...
into chemical activity.
Tendon
The process of mechanotransduction is explained for the lay-reader at http://bjsm.bmj.com/content/43/4/247.fullEar
One such mechanism is the opening of ion channels in the hair cellHair cell
Hair cells are the sensory receptors of both the auditory system and the vestibular system in all vertebrates. In mammals, the auditory hair cells are located within the organ of Corti on a thin basilar membrane in the cochlea of the inner ear...
s of the cochlea
Cochlea
The cochlea is the auditory portion of the inner ear. It is a spiral-shaped cavity in the bony labyrinth, making 2.5 turns around its axis, the modiolus....
in the inner 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
Oval window
The oval window is a membrane-covered opening which leads from the middle ear to the vestibule of the inner ear.Vibrations that come into contact with the tympanic membrane travel through the three ossicles and into the inner ear...
of the cochlea, in turn, generates a pressure field within the cochlear fluids, imparting a pressure differential across the basilar membrane
Basilar membrane
The basilar membrane within the cochlea of the inner ear is a stiff structural element that separates two liquid-filled tubes that run along the coil of the cochlea, the scala media and the scala tympani .-Function:...
. A sinusoidal pressure wave results in localized vibrations of the organ of Corti
Organ of Corti
The organ of Corti is the organ in the inner ear of mammals that contains auditory sensory cells, or "hair cells."The organ was named after the Italian anatomist Marquis Alfonso Giacomo Gaspare Corti , who conducted microscopic research of the mammaliean auditory system.-Structure and function:The...
: near the base for high frequencies, near the apex for low frequencies. The cochlea thus acts as an “acoustic prism”, distributing the energy of each Fourier
Fourier
Fourier most commonly refers to Joseph Fourier , French mathematician and physicist, or the mathematics, physics, and engineering terms named in his honor for his work on the concepts underlying them:In mathematics:...
component of a complex sound at different locations along its longitudinal axis. 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
Scala vestibuli
Scala vestibuli is a perilymph-filled cavity inside the cochlea of the inner ear that conducts sound vibrations to the scala media.It is separated from the scala media by Reissner's membrane and extends from the vestibule of the ear to the helicotrema where it joins scala tympani.-External links:* ...
and scala tympani
Scala tympani
Scala tympani is one of the perilymph-filled cavities in the cochlear labyrinth of the human ear. It is separated from the scala media by the basilar membrane, and it extends from the round window to the helicotrema, where it continues as scala vestibuli....
. Because this motion is accompanied by a shearing motion between the tectorial membrane
Tectorial membrane
Tectorial membrane can refer to:*Tectorial membrane *Tectorial membrane...
and the reticular lamina of the organ of Corti, the hair bundles that link the two are deflected, which initiates 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.
Basilar Membrane motion causes a shearing motion between the reticular lamina and the tectorial membrane, thereby activating the mechano-sensory apparatus of the hair bundle, which in turn generates a receptor potential
Receptor potential
Receptor potential, a type of graded potential, is the transmembrane potential difference of a sensory receptor.A receptor potential is often produced by sensory transduction. It is generally a depolarizing event resulting from inward current flow...
in the hair cells.
Thus the sound pressure wave is transduced to an electrical signal which can be processed as sound in higher parts of the auditory system
Auditory system
The auditory system is the sensory system for the sense of hearing.- Outer ear :The folds of cartilage surrounding the ear canal are called the pinna...
.
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.Cartilage
One of the main mechanical functions of articular cartilageCartilage
Cartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
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
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
(ECM), where they are subsequently dissipated and transmitted to chondrocytes (cartilage cells).
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
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
., Decreased mechanical loading over long periods, such as during extended bed-rest, causes a loss of matrix production. Static loads have been shown to be detrimental to biosynthesis 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. 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.
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 channel
Stretch-activated ion channel
Stretch-activated or stretch-gated ion channels are ion channels which open their pores in response to mechanical deformation of a neuron's plasma membrane. Stretch-activated channels were first observed in chick skeletal muscles by Falguni Guharay and Frederick Sachs in 1983 and the results were...
s (SAC), the hyaluronan receptor CD44
CD44
The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene.- Tissue distribution and isoforms :...
, annexin V (a collagen type II receptor), and integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
receptors (of which there exist several types on chondrocytes).
Integrin receptors have an extracellular domain that binds to the ECM proteins (collagen, fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
, laminin
Laminin
Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs...
, vitronectin
Vitronectin
Vitronectin also known as VTN is a protein that in humans is encoded by the VTN gene.The protein encoded by this gene is a member of the pexin family...
and osteopontin
Osteopontin
Osteopontin , also known as bone sialoprotein I , early T-lymphocyte activation , secreted phosphoprotein 1 , 2ar and Rickettsia resistance , is a human gene product, which is also conserved in other species...
), 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
Paxillin
Paxillin is a signal transduction adaptor protein discovered in 1990 in the laboratory of Keith Burridge and should not be confused with the neurotoxin paxilline. The C-terminal region of paxillin contains four LIM domains that target paxillin to focal adhesions, it is presumed through a direct...
, Pax, talin
Talin
Talin is a town in the Aragatsotn province of Armenia. It has a population of 5,371. The seventh century Talin Cathedral is located in the town.- History :...
, Tal and Shc
SHC
SHC may refer to:-Science:* Src homology 2 domain-containing, in structural biology, a structural domain in signal transduction proteins* SHC1, a human gene...
) are recruited to this cluster, which is called the focal adhesion
Focal adhesion
In cell biology, focal adhesions are specific types of large macromolecular assemblies through which both mechanical force and regulatory signals are transmitted. More precisely, they can be considered as sub-cellular macromolecules that mediate the regulatory effects In cell biology, focal...
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.
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 as well as changes in cAMP levels, actin re-organization and changes in the expression of genes which regulate cartilage ECM content.
More recent studies have hypothesized that chondrocyte primary cilium
Cilium
A cilium is an organelle found in eukaryotic cells. Cilia are slender protuberances that project from the much larger cell body....
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 (α2β1 and α3β1 ) have been identified on the upper shaft of the cilium, acting as anchors to the collagen matrix around it. However, in spite of results from recent studies (such as those from the lab of C.A. Poole) the mechanotransduction role of cilia remains to be proven.
It is important to examine the mechanotransduction pathways in chondrocytes since mechanical loading conditions which represent an excessive or injuruous 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.