WHAT IS MECHANOTRANSDUCTION?

Mechanotransduction refers to the process by which the body converts mechanical loading into cellular responses. These cellular responses, in turn, promote structural change. A classic example of mechanotransduction in action is bone adapting to load. A small, relatively weak bone can become larger and stronger in response to the appropriate load through the process of mechanotransduction.5

We searched PUBMED, EMBASE, MEDLINE, CINAHL, Google, Wikipedia, Melways and various library collections for the earliest reference to “mechanotransduction”. The first paper referenced under this term is by McElhaney et al in volume 1 of the Journal of Biomechanics, but the term is not used in that paper.6 Although there are 2441 citations in MEDLINE for mechanotransduction, the word is not found in the current edition of the Oxford English Dictionary. A useful formal definition of mechanotransduction might be “the processes whereby cells convert physiological mechanical stimuli into biochemical responses”. Mechanotransduction is generally broken down into three steps: (1) mechanocoupling, (2) cell–cell communication and (3) the effector response. To simplify this for patients, these same elements can be thought of as (1) the mechanical trigger or catalyst, (2) the communication throughout a tissue to distribute the loading message and (3) the response at the cellular level to effect the response—that is, the tissue “factory” that produces and assembles the necessary materials in the correct alignment. The communication at each stage occurs via cell signalling—an information network of messenger proteins, ion channels and lipids. In the following section, we detail these three steps using the tendon as an illustration; the fundamental processes also apply to other musculoskeletal tissues.

1. Mechanocoupling

Mechanocoupling refers to physical load (often shear or compression) causing a physical perturbation to cells that make up a tissue. For example, with every step the Achilles tendon receives tensile loads generated by three elements of the gastrocnemius–soleus complex and thus, the cells that make up the tendon experience tensile and shearing forces. Tendons can also experience compression forces (fig 1A,B) These forces elicit a deformation of the cell that can trigger a wide array of responses depending on the type, magnitude and duration of loading.7 The key to mechanocoupling, as the name suggests, is the direct or indirect physical perturbation of the cell, which is transformed into a variety of chemical signals both within and among cells.

Figure 1 Tendon cell undergoing (A,B) shear and (C) compression during a tendon-loading cycle.

2. Cell–cell communication

The previous paragraph illustrated mechanocoupling by focusing on a single cell, but let us draw back to examine a larger tissue area that contains thousands of cells embedded within an extracellular matrix (fig 2). The signalling proteins for this step include calcium and inositol triphosphate. The process of cell–cell communication is best understood by illustration (fig 2) and animation (supplementary slides online). The critical point is that stimulus in one location (location “1” in fig 2C) leads to a distant cell registering a new signal (location “2” in fig 2E) even though the distant cell does not receive a mechanical stimulus.7

Figure 2 Tendon tissue provides an example of cell–cell communication. (A) The intact tendon consists of extracellular matrix (including collagen) and specialised tendon cells (arrowheads). (B) Tendon with collagen removed to reveal the interconnecting cell network. Cells are physically in contact throughout the tendon, facilitating cell–cell communication. Gap junctions are the specialised regions where cells connect and communicate small charged particles. They can be identified by their specific protein connexin 43. (C–E) Time course of cell–cell communication from (C) beginning, through (D) the midpoint to (E) the end. The signalling proteins for this step include calcium (red spheres) and inositol triphosphate (IP3).

3. Effector cell response

To illustrate the third part of mechanotransduction (effector cell response), we focus on the boundary between the extracellular matrix and a single cell (fig 3). This process can be harnessed by mechanotherapy to promote tissue repair and remodelling. The main steps in mechanotransduction for connective tissues have been essentially unravelled for bone, but there remain unknown elements in the load-induced signalling pathways for muscle,8 9 tendon10–12 and articular cartilage.13 The reader seeking more detailed explanations of the process of protein synthesis generally is referred to classic texts (eg, Alberts et al14]). For more detailed explanations of mechanotransduction in connective tissue please consider the work of Ingber,15–18 Arnoczky,10 19 20 Banes,21–28 and Hart.29–32

Figure 3 Mechanical loading stimulates protein synthesis at the cellular level. (A) A larger scale image of the tendon cell network for orientation. We focus on one very small region. (B) Zooming in on this region reveals the cell membrane, the integrin proteins that bridge the intracellular and extra-cellular regions, and the cytoskeleton, which functions to maintain cell integrity and distribute mechanical load. The cell nucleus and the DNA are also illustrated. (C) With movement (shearing is illustrated), the integrin proteins activate at least two distinct pathways. (D) One involves the cytoskeleton that is in direct physical communication with the nucleus (ie, tugging the cytoskeleton sends a physical signal to the cell nucleus). Another pathway is triggered by integrins activating a series of biochemical signalling agents which are illustrated schematically. After a series of intermediate steps those biochemical signals also influence gene expression in the nucleus. (E). Once the cell nucleus receives the appropriate signals, normal cellular processes are engaged. mRNA is transcribed and shuttled to the endoplasmic reticulum in the cell cytoplasm, where it is translated into protein. The protein is secreted and incorporated into extracellular matrix. (F) In sum, the mechanical stimulus on the outside of the cell promotes intracellular processes leading to matrix remodelling.

To briefly summarise, it seems that mechanotransduction is an ongoing physiological process in the human body, just like respiration and circulation. Consider the skeleton as an example of a connective tissue; the body’s sensor is the osteocyte network and the process of regulating bone to load has been referred to as the “mechanostat”.33 34 In the absence of activity, the mechanotransduction signal is weak, so connective tissue is lost (eg, osteoporosis). When there are loads above the tissue’s set point, there is a stimulus through mechanotransduction so that the body adapts by increasing protein synthesis and adding tissue where possible (larger, stronger bone).33 34