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. 2024 May 25;39(7):814–820. doi: 10.1093/jbmr/zjae074

The role of mechanotransduction in tendon

Ryo Nakamichi 1,2,3, Hiroshi Asahara 4,5,✉
PMCID: PMC11301520  PMID: 38795012

Abstract

Tendons play an important role in the maintenance of motor function by connecting muscles and bones and transmitting forces. Particularly, the role of mechanical stress has primarily focused on the key mechanism of tendon homeostasis, with much research on this topic. With the recent development of molecular biological techniques, the mechanisms of mechanical stress sensing and signal transduction have been gradually elucidated with the identification of mechanosensor in tendon cells and the master regulator in tendon development. This review provides a comprehensive overview of the structure and function of tendon tissue, including the role for physical performance and the detailed mechanism of mechanotransduction in its regulation. An important lesson is that the role of mechanotransduction in tendon tissue is only partially clarified, indicating the complexity of the mechanisms of motor function and fueling increasing interest in uncovering these mechanisms.

Keywords: mechanotransduction, tendon, mechanosensor, transcription factor, physical performance

Introduction

Tendon tissue is the fibrous tissue that connects muscle to bone. It transmits muscle contraction force to bone, and this transmitted force induces joint motion, resulting in various movements and physical activities via affecting muscle contraction force.1 Generally, the higher the tendon elasticity, the greater the muscle shortening. The relationship between muscle contraction force and length varies depending on the region of the force–length relationship considering sarcomere length.2 In the ascending limb of the force–length curve, greater tendon elasticity shortens sarcomere length and increases muscle contraction force, whereas, in the descending limb, greater tendon elasticity shortens sarcomere length and decreases muscle contraction force.3 Thus, the mechanical properties of tendons affect physical performance through adjustment of muscle contraction force and joint movement induction.4 These indicate the importance of the mechanical properties of tendons for human activity. However, tendon tissue has inherently poor turnover and blood flow.5 Therefore, once damaged, tendon tissue does not fully regenerate.5 The injured area undergoes a process known as scar healing, but the tissue produced during this process has mechanical properties different from those of normal tissue, and normal tendon tissue function is not restored.5,6 As a result, even after a long period after tendon injury repair, an individual’s physical performance is not completely restored.7 Consequently, tendons lose their natural properties, leading to reduced physical performance and a lower quality of life. Therefore, research on the molecular mechanisms of tendon homeostasis has been conducted for maintaining healthy human activity.

In humans, sensory receptors such as taste, smell, sight, hearing, pain, and touch are responsible for sensing this outside world information. Such a system also exists at the cellular level; cells are known to have an intracellular information transduction system wherein various receptors on the cell membrane sense external information, and this information is transmitted to the inside of the cell for the final cellular response. One of the external types of information is mechanical stress, and the receptor responsible for sensing it is known as the mechanoreceptor. Mechanotransduction is the molecular mechanism of the process by which cells sense mechanical stress via mechanoreceptors and convert the signals into physiological and pathological responses and gene expression.8,9 In tendons, mechanotransduction has long been a research topic of interest. Recent advances in molecular biology research have increased our knowledge of mechanical stress, providing an opportunity to not only understand its role in tendons but also the importance of tendons in our daily lives. In this review, we summarize findings on the structure of tendons and their function in movement and the role of mechanotransduction in tendon homeostasis.

Tendon structure and mechanical properties

The smallest component of tendons is the tropocollagen monomer, which assembles to form a triple helix with intermolecular cross-links between the triple helices; these are known as collagen fibrils. The collagen fibril aggregates are covered by the endotenon to form collagen fibers, whose aggregation, in turn, forms fiber bundles, which are further covered by epitenon. These units are subsequently assembled and covered by a paratenon to produce tendons.10,11 The major matrix of tendons is type I collagen, while the endotenon, epitenon, and paratenon comprise type III collagen.12 These contain blood and lymphatic vessels and nerve tissue and are known to be involved in the maintenance of tenocytes.12 The noncollagenous matrices of tendons consist of various proteoglycans, including decorin (DCN), which is involved in the polymerization of collagen fibers; tenascin C (TNC), which binds to inactive growth factor [latent transforming growth factor-β (TGFβ)]; elastin, which is responsible for generating elasticity; and lubricin (PRG4) and aggrecan (ACAN), which are involved in fiber sliding.13–15 Tendon tissue can be divided into collagenous fascicles and noncollagenous interfascicular matrices (IFMs), and the mechanical properties of tendon tissue are determined by the combination of the mechanical properties of these two structures.16

The mechanical properties of tendon define the tendon’s function as a transmitter and store of energy.17 A typical stress–strain curve from a human tendon tensile test shows a toe region at the beginning, which is the result of crimp structure elongation of up to 2%. The next elongation region of up to 6% is known as the linear region, wherein collagen fibrils extend and shorten reversibly without fiber damage. The tilt of this region indicates the stiffness or Young’s modulus of the tendon tissue. With further elongation, tendon fibers gradually undergo microinjury, and the changes are irreversible, with tendon fiber rupture occurring at 8%-10% elongation18 (Figure 1). The results of this stress–strain curve excluded the effects of elongation velocity. However, in fact, tendon tissue has viscoelastic properties, which means that tendon behavior during motion depends on the strain velocity. At lower strain velocities, tendon tissue acts more as a viscous body, increasing energy loss and diminishing its effectiveness as a force transmitter. In contrast, at higher strain velocities, it acts more as an elastic body, enhancing its effectiveness as a force transmitter.

Figure 1.

Figure 1

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Representative stress–strain curve of mouse Achilles tendons. If the strain is <12%, the tendon will return to its original length when unloaded (toe region–linear region). At over 12% strain, the collagen fibers gradually develop microscopic failures. At over 16% stress, macroscopic failure occurs.

The components that produce viscoelasticity include collagen, noncollagenous matrices such as proteoglycans, the water that they attract, and the interactions between them.19,20  Prg4-knockout mice have increased tendon fascicle gliding resistance compared with that of wild-type mice, suggesting that PRG4 plays an important role in regulating tendon stiffness.21,22 Elastin, one of the major elastic proteins, is postulated to contribute to tendon elasticity through the combination of high resilience, large strains, and low stiffness, similar to rubber.23–25 Furthermore, energy-storing tendons, such as digital flexor tendons, contain more ACAN, biglycan (BGN), DCN, fibromodulin (FMOD), and cartilage oligomeric matrix protein (COMP) than positional tendons, such as digital extensor tendons.26–28 In summary, various tendon components are suggested to be involved in the mechanical properties of tendons, and the proportion of these components may determine the differences in the properties of different types of tendons.

Role of mechanical stress in tendon homeostasis

In tendons, appropriate mechanical stress, such as exercise, leads to an increased amount of type I collagen, resulting in tendon hypertrophy with the upregulation of stiffness without a change in Young’s modulus.29–31  Scx-GFP mice subjected to treadmill exercise displayed increased GFP expression in the epitenon of Achilles tendons, with upregulated Tenomodulin (Tnmd) and Col1a1 expression.32 Using tenocytes derived from mature tendons, type I collagen production is induced by an increase in TGFβ expression when moderate uniaxial mechanical stress is applied.33 Mechanical stress on tenocytes also maintains SCX expression through the TGFβ/Smad2/3 pathway.34 These findings suggest that the mechanical stress signal cascade leads to COL1A1 induction via SCX expression through the activation of the TGFβ signaling pathway in tenocytes and tendon progenitor cells.

Mohawk (MKX), another master transcription factor of tendon development, is also known as an important factor in tendon mechanotransduction. When tensile stress is applied to tendon stem/progenitor cells (TSPCs) derived from the patellar tendon of wild-type rats, the expression of tendon-related genes such as Mkx, Col1a1, and various proteoglycans increased.35,36 However, the expression of these tenogenic genes is not increased in TSPCs from the patellar tendon of Mkx knockout rats even if mechanical stress is applied, whereas the expression of Sox6 and Sox9, which are genes associated with cartilage differentiation, is increased.36 Furthermore, GTF2IRD1 is reportedly a regulator of MKX in response to mechanical stress.35 These findings suggest that mechano-signaling may regulate tenogenic gene expressions via the GTF2IRD1–MKX cascade in tenocytes and prevent chondrogenic degeneration.

In contrast, excessive mechanical stress is known to induce tendinopathy or tendon degeneration.37 Tendinopathic tendons have more cellular tissue with matrix changes compared with normal tendon tissue.38,39 Degenerative tendon cells exhibit morphological changes similar to chondrocyte cells, with increased production of large proteoglycans, including aggrecan and versican.38,39 Fibrous tissue changes to a disorganized collagen type, mainly type III collagen, with increased turnover, as well as neurovascular ingrowth.38,39 Previous studies have shown that these changes are derived from excessive mechanical stress. When rabbit-derived TSPCs were exposed to 4% tensile stress, type I or II collagens were produced, whereas when 8% tensile strain was applied, Sox9 or Runx2, chondrogenic or osteogenic markers, were upregulated, inducing degenerative changes in TSPCs.40 In another study using rabbit-derived tendon cells, excessive mechanical loading also elevated PGE2 levels, resulting in degenerative changes in tendon cells.41 At low concentrations, PGE2 contributes to the stabilization of tendon stem/progenitor cell properties, but at higher concentrations, it can shift these properties to those of osteoblasts.42

Less mechanical stress also induced tendon degeneration. When tendons are immobilized or placed in a mechanically stress-free environment, tendon cell shape, cell number, and collagen fiber arrangement are altered, eventually leading to tendon degeneration.43 In addition, tendon atrophy, weight loss, and reduction in stiffness and tensile strength also occur.44,45 Canine forelimbs suspended for 6 weeks displayed tendon atrophy with the decreased expression of several matrix components, including collagen type II, ACAN, DCN, and FMOD.46 Furthermore, the expression of various matrix metalloproteinases (MMPs) was increased, and tissue inhibitors of metalloproteinases were decreased, indicating the promotion of a catabolic effect in tendons in an environment with less mechanical stress.46

Taken together, mechanical stress has different effects on tendon homeostasis depending on the intensity. Appropriate mechanical stress plays a crucial role in promoting an anabolic effect on tenocytes by regulating the expression of tendon-specific genes. Nevertheless, excessive mechanical stress induces tendon degeneration through de-differentiation changes or inflammation, and nonmechanical stress has a catabolic effect on tendons.

The role of mechano-receptors in tendons

With the development of electrophysiological techniques, the function of mechanical stress-responsive ion channels in mechanoreceptors has gradually been identified. Currently, Degenerin (DEG)/epithelial sodium channel (ENAc), transient receptor potential (TRP), and PIEZO families are known as eukaryotic mechanical stress-responsive ion channels.47 The DEG/ENAc family comprises nonvoltage-gated Na+ channels that may contribute to pain perception and mechano-sensation.48 The role of the ENAc family in musculoskeletal systems has been rarely reported, but one report suggested that it is involved in cell volume regulation in chondrocytes.49 The TRP family consists of nonvoltage gated Ca2+ channels that exhibit diverse properties.50 They are classified into seven subfamilies (TRPA, TRPC, TRPML, TRPM, TRPN, TRPP, and TRPV), each known to sense various stresses.51  Trpv4 knockout mice develop lung, skin, and cardiac fibrosis, suggesting that TRPV4 has an important role in matrix regulation.52–54 Currently, a few studies have focused on the role of TRPV4 in the musculoskeletal system. One study demonstrated that TRPV4 affects the orientation of collagen production by regulating the tensile force of vinculin, one of the plasma membrane-lining proteins in mesenchymal stem cells.55 Other studies have shown that TRPV4 is involved in regulating the expression of Acan and Prg4 in annulus fibrosus, a connective tissue similar to tendons and ligaments.56 These findings suggest that TRPV4 is also involved in regulating collagen and noncollagen matrices and orientation in tendons, and further research is expected in the future.

PIEZO1 and 2 were mechanical stress-responsive Ca2+ ion channels.57,58 In genetic disease research, alterations in the functional activity of PIEZO1 are associated with specific diseases. For example, PIEZO1 loss-of-function (LOF) polymorphisms reportedly cause congenital lymphogranuloma dysplasia, while PIEZO1 gain-of-function (GOF) polymorphisms cause hereditary xerocytosis, suggesting that PIEZO1 activity must be tightly regulated in vivo.59–62 Previous reports suggest that PIEZO1, but not PIEZO2, plays a central role in musculoskeletal tissues. In bone, PIEZO1 is involved in endochondral ossification, and analysis of bone-specific PIEZO1/2 LOF mice showed that bone hypoplasia predominantly occurred in bone-specific PIEZO1 LOF mice compared with bone-specific PIEZO2 LOF mice.63,64 Furthermore, PIEZO1 is involved in the regulation of bone mineral density via osteoblasts since PIEZO1 participates in the regulation of Runx2 and collagen expression through calcineurin-mediated activation of NFATc1 and YAP.63,65–67 Moreover, during growth, PIEZO1 reportedly regulates bone growth by differentiating type H vessels into quiescent type L endothelium by regulating FAM20C expression in osteoblasts.68 In chondrocytes, PIEZO1-mediated mechanotransduction has been shown to induce cell death, suggesting a relationship between inflammation-induced promotion of PIEZO1 expression and osteoarthritis in cartilage.69,70

Very recently, PIEZO1 was identified as the main mechanical stress-responsive Ca2+ channel receptor in tendons. When each known mechanical stress-induced Ca2+ channel receptor was knocked down in rat tendon cells, Piezo1-knock-down cells exhibited the greatest reduction in Ca2+ influx.71 In addition, single-cell analysis of mouse tendon tissue-derived cells showed that Piezo1 was highly expressed among various receptors in clusters with a high expression of Mkx and Scx.72

Phenotype analysis has also been performed using transgenic mice with a Cre-dependent GOF mutation in PIEZO1 (R2482H).71,72 Tendon tissue from Piezo1 GOF mice crossed with CMV-Cre (systemic) or Scx-Cre (tendon-specific) mice showed a significantly increased transverse width of Achilles tendons.72 Transcriptome and immunohistology analysis of Achilles tendons from tendon-specific Piezo1 GOF mice showed increased expression of MKX and SCX, matrices forming fascicles, including type I collagen, and noncollagenous matrices forming IFM, including Tnmd, Dcn, Fmod, and Prg4.72 In human tenocytes, Ca2+ influx due to the PIEZO1 channel induces the activation of the transcription factor NFATC via calcineurin activation, which in turn induces the expression of MKX and SCX.72 Taken together, these results suggest that the mechanical stress-PIEZO1-MKX/SCX cascade in tenocytes induces structural modification of tendon tissue (Figure 2).

Figure 2.

Figure 2

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Schema of the mechanotransduction mechanism of tendons, as currently known. Appropriate mechanical loading enhances anabolism through the PIEZO1-MKX/SCX cascade (Created with BioRender.com).

Role of tendon mechanoreceptors in physical performance

Notably, Piezo1 GOF mice showed enhanced instantaneous power, such as in jumping and running speed.72 Furthermore, analysis of various tissue-specific Piezo1 GOF mice revealed that this instantaneous power enhancement is due to PIEZO1 activation in tendon tissues.72 As one of the mechanisms of physical performance enhancement, the stored energy of tendons upon activation of PIEZO1 is increased compared with that in wild-type mice.72 Since the expressions of several collagen and noncollagen matrices involved in tendon extensibility are upregulated in Piezo1 GOF mice, changes in their content are expected to play a role in determining the mechanical properties of tendons.21–26,73 An Achilles tendon tensile test in tendon-specific Piezo1 GOF male mice showed no difference in stiffness but a significant increase in the elastic limit compared with those in control mice.72 In contrast, plantaris tendon and tail tendon tensile tests in systemic Piezo1 GOF mice demonstrated increased stiffness and maximum force and no significant increase in the elastic limit.71 This discrepancy may be dependent on differences in the genotype of the mice, sex, and the type of tendon evaluated. At the same time, the calculation of kinetic energy during jumping is speculated to indicate that unknown factors other than the stored energy of tendons are at play.72 This suggests that the relationship between structural changes in tendons and physical performance entails mechanisms that are not yet clear.

In 2018, E756del was reported as a genetic polymorphism of PIEZO1 that is relatively concentrated in West Africans and African Americans.74 This polymorphism is a mild GOF mutation relative to the R2456H polymorphism, which causes hereditary xerocytosis.74 Notably, West Africans, including African Americans and Jamaicans, are also known to be the racial group with the greatest number of elite sprinters. A clinical study of ~200 Jamaicans compared the frequency of the E756del polymorphism between sprinters, and the general population showed that 54% of Jamaican sprinters possessed E756del, which is a significantly higher proportion than that of the general population at 33%.72 In a clinical study of 65 African Americans living in the USA, the rate of increase in jumping distance for two types of jumps, drop and countermovement jumps, was higher in the group with the E756del polymorphism.71 However, when similar research was performed on 77 West or Central Africans living in Zurich, no clear differences were observed between the groups with or without E756del.75 At present, human studies are inconclusive regarding whether PIEZO1 functional activity affects physical performance, suggesting the need for future large-scale studies.

Conclusions and future directions

This review summarizes current knowledge of the mechanobiology of tendons. It is suggested that mechanical stress can enhance the anabolic effects of tenocytes, considering appropriate forces, which can alter the mechanical properties of tendon tissue and may also affect physical performance. The mechanism by which this systemic effect occurs has only been clarified partially, and future research should include the possibility of a linkage to organs, such as muscles or nerves, or even with organs throughout the body. Furthermore, it will be a future challenge to identify the differences in the mechanisms by which mechanical stress is sensed as “appropriate” or “excessive/less” for the tenocytes. PIEZO1-MKX/SCX cascade is considered to promote anabolism as “appropriate” mechano-sensing; however, the systemic functional activity of PIEZO1 is also known to cause disease; that strict regulation or tissue-specific regulation of its activity would be “appropriate” for the whole body. Clarification of future challenges is anticipated to lead to applications in enhancing physical performance and the extension of healthy life expectancy.

Author contributions

Ryo Nakamichi (Writing—original draft, Writing—review & editing) and Hiroshi Asahara (Writing—original draft, Writing—review & editing)

Funding

This work was made possible by funding provided by JSPS KAKENHI (Grant Numbers JP20H05696), AMED (Grant Number JP22gm0010009, JP22ym0126805), and National Institutes of Health (Grant Number AR080127 to H.A.).

Conflicts of interest

The authors have no conflicts of interest to declare related to this article.

Contributor Information

Ryo Nakamichi, Department of Molecular and Cellular Biology, Scripps Research, 10550 North Torrey Pines Road, MBB-102, La Jolla, CA 92037, United States; Department of Systems Biomedicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo 113-8510, Japan; Department of Orthopaedic Surgery, Okayama University hospital, 2-5-1 Shikata-Cho, Kita-Ku, Okayama 700-8558, Japan.

Hiroshi Asahara, Department of Molecular and Cellular Biology, Scripps Research, 10550 North Torrey Pines Road, MBB-102, La Jolla, CA 92037, United States; Department of Systems Biomedicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo 113-8510, Japan.

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