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Mechanotransduction gone awry

Nature Reviews Molecular Cell Biology volume 10, pages 63–73 (2009)Cite this article

Key Points

  • Mechanotransduction describes the cellular processes that translate mechanical inputs into biochemical signals and can modulate cellular functions as diverse as migration, proliferation, differentiation and apoptosis.

  • Mechanotransduction is essential in the development and maintenance of all tissues, but is particularly important in mechanically-stressed tissues such as muscle, bone, cartilage and blood vessels, as these require adaptive responses to quickly adjust to varying loading conditions.

  • Changes in cellular or extracellular structure, the cellular mechanosensing process itself or in the relevant downstream signalling pathways can result in altered and abnormal mechanotransduction and can lead to disease.

  • Diseases associated with disturbed mechanotransduction signalling include developmental defects, loss of hearing, muscular dystrophies, cardiac myopathies, defects in bone and cartilage, axial myopia, glaucoma, arteriosclerosis and cancer.

  • A common denominator of many mechanobiology diseases is a disruption in the intricate force transmission between the extracellular matrix (ECM), the cytoskeleton and the nuclear interior.

  • Sudden changes in ECM mechanics, ECM remodelling and the resultant disturbance in cytoskeletal tension and mechanotransduction signalling have emerged as important factors that can promote malignant transformation, tumorigenesis and metastasis.

Abstract

Cells sense their physical surroundings through mechanotransduction — that is, by translating mechanical forces and deformations into biochemical signals such as changes in intracellular calcium concentration or by activating diverse signalling pathways. In turn, these signals can adjust cellular and extracellular structure. This mechanosensitive feedback modulates cellular functions as diverse as migration, proliferation, differentiation and apoptosis, and is crucial for organ development and homeostasis. Consequently, defects in mechanotransduction — often caused by mutations or misregulation of proteins that disturb cellular or extracellular mechanics — are implicated in the development of various diseases, ranging from muscular dystrophies and cardiomyopathies to cancer progression and metastasis.

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Figure 1: Mechanotransduction in hair cells.
Figure 2: Force transmission between the extracellular matrix and the nucleus.
Figure 3: Unifying characteristics of mechanotransduction disorders.
Figure 4: Cardiac mechanotransduction signalling.
Figure 5: Mechanotransduction in cancer cells.

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Acknowledgements

We apologize to all those authors whose papers we could not cite because of space limitations. We thank R. T. Lee and P. Patwari for insightful discussions and helpful comments. This work was supported by National Institutes of Health grants HL082792, NS059348, the American Heart Association grant 0635359N and a research grant from the Progeria Research Foundation.

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  1. Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 65 Landsdowne Street, Room 283, Cambridge, 02139, Massachusetts, USA

    Diana E. Jaalouk & Jan Lammerding

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Correspondence to Jan Lammerding.

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DATABASES

OMIM

Duchenne muscular dystrophy

Emery–Dreifuss muscular dystrophy

Hutchinson–Gilford progeria syndrome

Kartagener's syndrome

FURTHER INFORMATION

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Glossary

Sensory cells

Cells involved in the sensory reception of touch or hearing, often using specialized cellular structures such as hair bundles or proteins (for example, stretch-activated ion channels) to detect applied forces and deformations.

Vascular smooth muscle cells

Non-striated muscle cells found in the medial layer of arteries and arterioles. These cells are involved in regulating blood pressure and vessel tone.

Mechanosensitive proteins

Proteins that are directly involved in sensing forces or deformations. Microscopic forces result in conformational changes in these proteins, thereby altering their affinity to binding partners or ion conductivity and initiating downstream signalling pathways.

Stereocilia

Finger-like cytoplasmic extensions that project from the apical end of the inner ear's hair cells into the cochlear fluid. Stereocilia respond to fluid movement and changes in fluid pressure to mediate various sensory functions, including hearing.

Motor proteins

Proteins that generate the intracellular forces that are required for molecular transport or cell tension and contractility. Include dynein and kinesin.

Cilia

Hair-like projections on the outer surface of some cell types and unicellular organisms. Beating in unison in wave-like motion, cilia serve multiple functions including mechanosensing, motility and feeding.

Deafness genes

A set of genes, including the cadherin-23 gene, that encode tip link proteins, which are found in the hair cells in the inner ear and play a central role in the conversion of physical stimuli into electrochemical signals. Mutations in these genes can cause deafness.

Stretch-sensitive ion channels

Ion channels that can change their conformation from closed to open in response to mechanical strain in the membrane.

Sarcomeres

Basic functional units in striated muscle cells, consisting mostly of thick myosin filaments and thin actin filaments to generate forces.

Aortic stenosis

A condition that is characterized by abnormal narrowing of the valve opening between the left ventricle and the aorta in the heart, restricting blood flow and impeding the ability of the heart to pump blood to the body.

Ventricular wall stress

The mechanical stress, that is force per unit area, in the myocardium. Decrease in wall thickness, following loss of myocytes after infarction can result in increased left ventricular stress and can damage the remaining myocytes.

Interstitial fibrosis

A progressive condition that is characterized by fibrous connective tissue replacing normal tissue, such as muscle, that is lost by injury or by infection and infiltration of inflammatory cells into the small spaces between tissues.

Haemodynamic load

The forces that are generated from cardiac output and physical resistances due to the flow of blood in circulation.

Glaucoma

A disease in which the optic nerve is permanently damaged due to abnormally high fluid pressure in the eye. Results in impaired or complete loss of vision.

Axial myopia

Near- or short-sightedness associated with an increase in the eye's axial length.

Intraocular pressure

The pressure inside the eyeball that is generated by resistance to the outward fluid flow of aqueous humour. This pressure helps maintain the shape of the eye, but can result in glaucoma if it is too high.

Focal adhesions

Dynamic protein complexes at the plasma membrane that connect the extracellular matrix to the actin cytoskeleton. Focal adhesions consist of integrins, talin, paxillin and signalling molecules such as focal adhesion kinase. Several of these proteins are thought to act as mechanosensors and to participate in mechanotransduction signalling.

Pleural effusions

Fluids that collect in the space between the lungs and the chest wall.

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Jaalouk, D., Lammerding, J. Mechanotransduction gone awry. Nat Rev Mol Cell Biol 10, 63–73 (2009). https://doi.org/10.1038/nrm2597

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