Mechanical loads induce changes in the structure, composition, and function of living tissues. Cells in tissues are responsible for these changes, which cause physiological or pathological alterations in the extracellular matrix (ECM). This article provides an introductory review of the mechanobiology of load-sensitive cells in vivo, which include fibroblasts, chondrocytes, osteoblasts, endothelial cells, and smooth muscle cells. Many studies have shown that mechanical loads affect diverse cellular functions, such as cell proliferation, ECM gene and protein expression, and the production of soluble factors. Major cellular components involved in the mechanotransduction mechanisms include the cytoskeleton, integrins, G proteins, receptor tyrosine kinases, mitogen-activated protein kinases, and stretch-activated ion channels. Future research in the area of cell mechanobiology will require novel experimental and theoretical methodologies to determine the type and magnitude of the forces experienced at the cellular and sub-cellular levels and to identify the force sensors/receptors that initiate the cascade of cellular and molecular events.

Mechanical loads placed on connective tissues alter gene expression in fibroblasts through mechanotransduction mechanisms by which cells convert mechanical signals into cellular biological events, such as gene expression of extracellular matrix components (e.g., collagen). This mechanical regulation of ECM gene expression affords maintenance of connective tissue homeostasis. However, mechanical loads can also interfere with homeostatic cellular gene expression and consequently cause the pathogenesis of connective tissue diseases such as tendinopathy and osteoarthritis. Therefore, the regulation of gene expression by mechanical loads is closely related to connective tissue physiology and pathology. This article reviews the effects of various mechanical loading conditions on gene regulation in fibroblasts and discusses several mechanotransduction mechanisms. Future research directions in mechanoregulation of gene expression are also suggested.

Tendinopathy is accompanied by inflammation, tendon matrix degradation, or both. Inflammatory cytokine IL-1beta, which is a potent inflammatory mediator, is likely present within the tendon. The purpose of this study was to determine the biological impact of IL-1beta on tendon fibroblasts by assessing the expression of cPLA(2), COX-2, PGE(2) and its receptors (EPs), collagen type-I, and MMPs. We also studied the role of the p38 MAPK pathway in IL-1beta-induced catabolic effects. We found that IL-1beta increased the expression levels of cPLA(2) and COX-2, and also increased the secretion of PGE(2). Induction of MMPs, such as MMP-1 and MMP-3 at the mRNA level, was also observed after stimulation with IL-1beta. Furthermore, the presence of IL-1beta significantly decreased the level of collagen type-I mRNA in tendon fibroblasts. These effects were found to be mediated by selective upregulation of EP(4) receptor, which is a member of G-protein-coupled receptor that transduces the PGE(2) signal. Blocking EP(4) receptor by a specific chemical inhibitor abolished IL-1beta-induced catabolic effects. These results suggest that IL-1beta-induced catabolic action on tendon fibroblasts occurs via the upregulation of two key inflammatory mediators, cPLA(2) and COX-2, which are responsible for the synthesis of PGE(2). IL-1beta further stimulates the expression of EP(4) receptor, suggesting positive feedback regulation which may lead to accelerated catabolic processes in tendon fibroblasts. Studies using pathway-specific chemical inhibitors suggest that the p38 MAPK pathway is the key signaling cascade transducing IL-1beta-mediated catabolic effects. Collectively, our findings suggest that the EP(4) receptor mediates the IL-1beta-induced catabolic metabolism via the p38 MAPK pathway in human tendon fibroblasts and may play a major role in the tendon's degenerative changes often seen in the later stages of tendinopathy.

No abstract

Tendons are unique in the sense that they are constantly subjected to large mechanical loads and that they contain tendon-specific cells, including tenocytes and tendon stem/progenitor cells. The responses of these cells to mechanical loads can be anabolic or catabolic and as a result, change the biological properties of the tendon itself that may be beneficial or detrimental. On the other hand, aging also induces aberrant changes in cellular expression of various genes and production of various types of matrix proteins in the tendon, and consequently lead to tendon degeneration and impaired healing in aging tendons; both could be improved by moderate physiological mechanical loading such as treadmill running. This article gives an overview on the mechanobiology research of young and aging animal tendons using treadmill running model. The challenges in such treadmill running studies are also discussed. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:557-565, 2018.