Biomechan Model Mechanobiol (2006) 5: 1–16 DOI 10.1007/s10237-005-0012-z REVIEW J.H.-C. Wang · B.P. Thampatty An introductory review of cell mechanobiology Received: 28 January 2005 / Accepted: 8 December 2005 / Published online: 28 January 2006 © Springer-Verlag 2006 Abstract Mechanical loads induce changes in the structure, lung tissue is stretched cyclically due to breathing and is composition, and function of living tissues. Cells in tissues exposed to mechanical forces from blood flow and surface are responsible for these changes, which cause physiological tension while dermal tissues are subjected to tensile, com- or pathological alterations in the extracellular matrix (ECM). pressive, and shearing forces. The heart is also continuously This article provides an introductory review of the mechano- subjected to mechanical forces due to changes in blood vol- biology of load-sensitive cells in vivo, which include fibro- ume and pressure. As a final example, one’s senses of touch blasts, chondrocytes, osteoblasts, endothelial cells, and smooth and hearing are initiated by forces as well. muscle cells. Many studies have shown that mechanical loads It has been known for many years that tissues grow and affect diverse cellular functions, such as cell proliferation, remodel in response to changes in mechanical forces. A typ- ECM gene and protein expression, and the production of ical example is bone, which changes its shape, density, and soluble factors. Major cellular components involved in the stiffness when its mechanical loading conditions are altered mechanotransduction mechanisms include the cytoskeleton, (Turner and Pavalko 1998; Mullender et al. 2004). Simi- integrins, G proteins, receptor tyrosine kinases, mitogen-acti- larly, blood vessels remodel themselves in response to al- vated protein kinases, and stretch-activated ion channels. Fu- tered blood pressure and shear stress (Owens 1996; Williams ture research in the area of cell mechanobiology will require B 1998). It is the cells in tissues that are responsible for novel experimental and theoretical methodologies to deter- this remodeling in response to mechanical forces. It is now mine the type and magnitude of the forces experienced at the well recognized that mechanical forces play a fundamen- cellular and sub-cellular levels and to identify the force sen- tal role in the regulation of cell functions, including gene sors/receptors that initiate the cascade of cellular and molec- induction, protein synthesis, cell growth, death, and differ- ular events. entiation, which are essential to maintain tissue homeostasis. Conversely, abnormal mechanical loading conditions alter cellular function and change the structure and composition of the extracellular matrix (ECM), eventually leading to tissue 1 Introduction or organ pathologies such as osteoporosis, osteoarthritis, ten- dinopathy, atherosclerosis, and fibrosis in the bone, cartilage, Human beings experience diverse mechanical forces from a tendon, vessels, heart, lung, and skin (Ross 1986; Chicurel wide variety of sources. Gravity is an example of a ubiquitous et al. 1998; Grodzinsky et al. 2000; Ireland et al. 2001; Riley force that acts on the body. Another example is tensile mus- et al. 2002; Ingber 2003; Bag et al. 2004; Borer et al. 2004; cular forces that act on bones through tendons to move joints Eckes and Krieg 2004; Lammerding et al. 2004). and permit human locomotion. Other examples of mechani- Although it is clear that cell response to mechanical forces cal forces include compressive loads on cartilage and bones is closely related to tissue physiology and pathology, it re- during walking and exercise as well as blood pressure and mains unclear how the cells sense mechanical forces and shear stresses on the vessels due to blood flow. Similarly, convert such “mechanical signals” into biological responses. J.H.-C. Wang (B) · B.P. Thampatty This is further complicated by the fact that cells are highly MechanoBiology Laboratory, Departments of Orthopaedic Surgery, dynamic and their complex structure changes in response to Bioengineering and Mechanical Engineering, mechanical forces. Mechanobiology is an interdisciplinary University of Pittsburgh 210 Lothrop St., BST, E1640, study that is concerned with the cells’ biological responses Pittsburgh, PA 15213, USA E-mail: [email protected] to mechanical loads and the mechanotransduction mecha- Tel.: +1-412-648-9102 nisms by which these loads are transduced into a cascade of Fax: +1-412-648-8548 cellular and molecular events (Ingber 1998). Knowledge of 2 J.H.-C. Wang, B.P. Thampatty these mechanotransduction mechanisms will aid in a better tendons and ligaments are dominated by fibroblasts, which understanding of the physiological responses of various tis- perform many vital functions during development and af- sues, such as the effects of training or disuse on tendons and ter maturity (Camelliti et al. 2005). These functions include ligaments (Woo et al. 1982; Tipton et al. 1986). This com- organizing and maintaining connective tissues during devel- prehension will also help elucidate the pathogenesis of many opment and repairing wounds during wound healing (Math- diseases caused by mechanical loads such as tendinopathy ews 1975). Fibroblasts synthesize collagen types I and III and (Wang 2005), and hence aid in developing new therapeutic minor amounts of collagens IV, V, VI, elastin, laminin, pro- approaches to treat these pathological conditions more effec- teoglycans and glycosaminoglycans (GAGs)(Camelliti et al. tively. 2005), which are the structural constituents that constitute the This article provides an introductory review of the me- ECM of many tissues, including tendons, ligaments, and skin. chanobiology of load-sensitive cells in vivo, including fi- Finally, fibroblasts produce various factors such as cytokines broblasts, osteoblasts, chondrocytes, endothelial cells, and [e.g., tumor necrosis factor-α (TNF-α)], growth factors [e.g., smooth muscle cells (SMCs). We focus on a discussion of transforming growth factor-β (TGF-β)], and matrix metal- ECM gene and protein expression as well as the produc- loproteinases (MMPs), which are all involved in connective tion of soluble factors by these cells in response to various tissue maintenance, repair, and remodeling (MacKenna et al. mechanical forces in vitro. We also describe interactions be- 2000). tween mechanical load and soluble factors and the effects Chondrocytes are found in another type of load-bear- of mechanical loading on tissue engineering constructs. This ing tissue, articular cartilage. Chondrocytes proliferate and is followed by an overview of the cellular mechanotrans- differentiate in multiple stages to create the ECM that forms duction mechanisms before concluding with future research this complex tissue (Stockwell 1979; Erlebacher et al. 1995). directions in the area of cell mechanobiology. At each stage of differentiation, chondrocytes express and secrete a distinct class of collagens, proteoglycans, and other ECM molecules (Karsenty and Wagner 2002; Mao and Nah 2 Cells and the ECM 2004). At the proliferating stage, chondrocytes synthesize two major macromolecules: type II collagen and a large aggre- 2.1 Cell structure and function gating proteoglycan, aggrecan. These molecules interact with water through ionic and hydrogen bonding to form a stabi- All organisms are composed of cells, which are the basic lized load-bearing matrix that resists compressive and tensile structural and functional unit of life. All cells are composed forces. The cross-linked type II collagen fibrils allow carti- of a plasma membrane, cytoplasm, nucleus, and other sub- lage to resist shear stress as well as compressive stress (Lane cellular components. The plasma membrane consists of a Smith et al. 2000). A number of minor forms of collagen, such phospholipid bilayer, with hydrophilic heads and hydropho- as types III, VI, XII, XIV, and XVI, are also synthesized by bic tails, in which integral membrane proteins are embedded chondrocytes (Aigner and Stove 2003). (Alberts 1989). The structure of the membrane allows cells It is known that bone bears tension, compression, and tor- to perform various necessary tasks: movement of substances sion in vivo. Therefore, bone cells such as osteoblasts are sub- in and out of the cells, antigen recognition, and maintenance jected to diverse mechanical forces. Osteoblasts are respon- of cell attachments, for example. The cytoplasm contains the sible for bone formation and are derived from mesenchymal cytoskeleton and various organelles, including the nucleus, cells found in bone marrow (Aubin and Triffitt 2002). These ribosomes, endoplasmic reticulum, and mitochondria. These cells play a central role in creating and maintaining skel- organelles carry out the basic functions of the cell, including etal architecture. They secrete a mixture of ECM proteins, gene expression and protein synthesis. including type I collagen, which is the major component rep- The human body has more than 200 different types of resenting about 90% of the bone matrix, as well as proteogly- cells that vary in size, shape, and function. The characteris- cans and glycoproteins (Mackie 2003; Kartsogiannis and Ng tics of the different cells are determined by the nature of pro- 2004). In addition, osteoblasts produce growth factors such teins, which carry out most of the cell activities. Cells arise as TGF-β and bone morphogenetic proteins. in the body from stem cells and become specialized for one Forming the inner