Review
Mechanobiology of tendon

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Abstract

Tendons are able to respond to mechanical forces by altering their structure, composition, and mechanical properties—a process called tissue mechanical adaptation. The fact that mechanical adaptation is effected by cells in tendons is clearly understood; however, how cells sense mechanical forces and convert them into biochemical signals that ultimately lead to tendon adaptive physiological or pathological changes is not well understood. Mechanobiology is an interdisciplinary study that can enhance our understanding of mechanotransduction mechanisms at the tissue, cellular, and molecular levels. The purpose of this article is to provide an overview of tendon mechanobiology. The discussion begins with the mechanical forces acting on tendons in vivo, tendon structure and composition, and its mechanical properties. Then the tendon's response to exercise, disuse, and overuse are presented, followed by a discussion of tendon healing and the role of mechanical loading and fibroblast contraction in tissue healing. Next, mechanobiological responses of tendon fibroblasts to repetitive mechanical loading conditions are presented, and major cellular mechanotransduction mechanisms are briefly reviewed. Finally, future research directions in tendon mechanobiology research are discussed.

Introduction

Tendons are mechanically responsible for transmitting muscle forces to bone, and in doing so, permit locomotion and enhance joint stability. Moreover, tendons are a living tissue and respond to mechanical forces by changing their metabolism as well as their structural and mechanical properties. For example, tendons exhibit increased cross-sectional area and tensile strength, and tendon fibroblasts increase the production of collagen type I in response to appropriate physical training (Suominen et al., 1980; Michna and Hartmann, 1989; Langberg et al., 2001; Tipton et al., 1975). However, inappropriate physical training leads to tendon overuse injuries, or tendinopathy (Khan and Maffuli, 1998; Maffulli et al., 1998), and excessive repetitive stretching of human patellar tendon fibroblasts (HPTFs) increases the production of inflammatory mediators, such as prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) (Li et al., 2004; Wang et al., 2001).

The ability of connective tissues like tendons to alter their structure in response to mechanical loading is referred to as tissue mechanical adaptation. There is little doubt that the adaptation is effected by cells in tissues. However, the mechanotransduction mechanisms by which cells sense mechanical forces and convert them into the biochemical signals that ultimately lead to tissue adaptive physiological or pathological changes are still not completely understood. Mechanobiology, the interdisciplinary study of changes in tissue structure and function, will play an important role in our understanding of mechanotransduction mechanisms at the cellular and molecular levels.

The goal of this review is to provide an overview of tendon mechanobiology. First, we will describe the mechanical forces acting on tendons in vivo, tendon structure and composition, and mechanical properties. We will then review the tendon's response to training (or exercise), disuse, and overuse. This will be followed by introducing tendon healing and the roles of mechanical loading and fibroblast contraction in tissue healing. Next, we will review the mechanobiological responses of tendon fibroblasts to repetitive mechanical loading conditions. Finally, we will briefly review the major mechanotransduction mechanisms proposed in the literature and discuss future directions in tendon mechanobiology research.

Section snippets

Tendon forces in vivo

Forces generated in muscles are transmitted to bone through tendons, which makes joint and limb movement possible. To do this effectively, tendons must bear large forces. In humans, it has been estimated that the peak force transmitted through the Achilles tendon during running was 9 kN, which is equivalent to 12.5 times the body weight (Komi, 1990; Komi et al., 1992). In human hand flexor tendons (Schuind et al., 1992), it was shown that the intratendinous force of the tendon depends on whether

Tendon structure

The tendon has a multi-unit hierarchical structure composed of collagen molecules, fibrils, fiber bundles, fascicles and tendon units that run parallel to the tendon's long axis (Fig. 1). The fibril is the smallest tendon structural unit; it consists largely of rod-like collagen molecules aligned end-to-end in a quarter-staggered array. Fibril diameters vary from 10 to 500 nm, depending on species, age, and sample location. Young animals have uniformly small fibrils, whereas mature animals

Training and mobilization effects on tendons

Tendons change structure in response to the functional demands on them. In rabbits that exercised for 40 weeks, the ultimate load and energy absorbed at failure of the rabbit peroneus brevis tendon were higher than those of rabbits without exercise (Viidik, 1967, Viidik, 1969. Also, running exercise for 12 months increased the strength of the tendon insertion site in swine (Woo et al., 1981). In mice exercised on a treadmill for 1 week, the number and size of collagen fibrils, and

Tendon healing processes

Tendon healing can be largely divided into three overlapping phases: the inflammatory, repairing, and remodeling phases (Frank et al., 1994; Woo et al., 1999). In the initial inflammatory phase, which lasts about 24 h, erythrocytes, platelets, and inflammatory cells (e.g., neutrophils, monocytes, and macrophages) migrate to the wound site and clean the site of necrotic materials by phagocytosis. In the mean time, these cells release vasoactive and chemotactic factors, which recruit tendon

The effects of mechanical loading on cells

As discussed in the preceding sections, tendons respond to altered mechanical loading conditions by changing their structure, composition, and mechanical properties. Fibroblasts within the tendons, which are their dominant cell type, are responsible for these changes by altering the expression of ECM proteins (Banes et al., 1999; Benjamin and Ralphs, 2000; Kjaer, 2004).

Because experimental conditions can be tightly controlled, in vitro model systems are often used to study responses of tendon

Mechanotransduction

As described in previous sections, tendons have the ability to adapt to altered mechanical loading conditions by changing their structure and composition. Cells in the tendon are responsible for the tendon's adaptive response. Tendon cells respond to mechanical forces by altering gene expression, protein synthesis, and cell phenotype. These early adaptive responses may proceed and initiate long-term tendon structure modifications and thus lead to changes in the tendon's mechanical properties.

Summary

Tendons are responsible for transmitting muscle-derived forces to bone and as a result, are subjected to dynamic mechanical loads. Although the effects of mechanical loading on tendons have been recognized for many years, little is known concerning the effects of mechanical forces on tendon cells and the mechanisms of mechanotransduction. During the last few decades, the rapid development of cell and molecular technologies has made it possible to investigate mechanobiological responses and

Acknowledgments

I thank Mr. Zachary Britton, Ms. Charu Agarwal, and Drs. Michael Iosifidis and Padma Thampatty for their assistance in preparing this review. I also gratefully acknowledge the funding support of the Arthritis Investigator Award from the Arthritis Foundation, Biomedical Engineering Research Grant from the Whitaker Foundation, and NIH Grant AR049921.

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