J Appl Physiol 95: 2134-2141, 2003;
doi:10.1152/japplphysiol.00429.2003
8750-7587/03 $5.00
HIGHLIGHTED TOPICS
Physiology of Aging
Invited Review: Role of mechanophysiology in aging of ECM: effects of changes in mechanochemical transduction
Frederick H. Silver,1
Dale DeVore,2 and
Lorraine M. Siperko3
1Department of Pathology and Laboratory Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854; 2Xium, LLC, Chelmsford, Massachusetts 01824; and 3Department of Biochemistry and Molecular Pathology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio 44272
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ABSTRACT
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Mechanical forces play a role in the development and evolution of extracellular matrices (ECMs) found in connective tissue. Gravitational forces acting on mammalian tissues increase the net muscle forces required for movement of vertebrates. As body mass increases during development, musculoskeletal tissues and other ECMs are able to adapt their size to meet the increased mechanical requirements. However, the control mechanisms that allow for rapid growth in tissue size during development are altered during maturation and aging. The purpose of this mini-review is to examine the relationship between mechanical loading and cellular events that are associated with downregulation of mechanochemical transduction, which appears to contribute to aging of connective tissue. These changes result from decreases in growth factor and hormone levels, as well as decreased activation of the phosphorelay system that controls cell division, gene expression, and protein synthesis. Studies pertaining to the interactions among mechanical forces, growth factors, hormones, and their receptors will better define the relationship between mechanochemical transduction processes and cellular behavior in aging tissues.
phosphorelay system; extracellular matrix; connective tissue; collagen; mechanical forces
EXTRACELLULAR MATRICES (ECMs), which make up connective tissue found in vertebrates, are the primary structural materials that serve to maintain tissue shape. They aid in locomotion, transmit and distribute mechanical loads, prevent premature mechanical failure, partition cells and tissues into functional units, act as scaffolds that define tissue and organ architecture, and act as storage and dissipative devices for elastic energy and as the substrate for cell adhesion and growth and differentiation of a variety of cell types (Refs. 1, 2, 38, 43, 46, 47). The composition, structure, and mechanical properties of ECM, as well as the repair responses seen in connective tissue, are reported to change with age (21, 31, 47). Factors such as ultraviolet light exposure, mechanical wear and tear, inflammation, and changes in the responsiveness of cells to hormones and growth factors clearly play important roles in aging processes associated with connective tissue (6, 8, 14, 49, 52, 53); however, little attention has been paid to the role of mechanical forces and how changes in mechanical loading may affect the balance between tissue anabolism and catabolism associated with aging. The purpose of this mini-review is to consider how external mechanical loading and internal mechanical loading influence mechanochemical transduction processes in ECMs and how the synergism between mechanochemical transduction and changes in levels of growth factors, hormones, inflammatory mediators, and other signaling molecules may contribute to aging of connective tissue.
Although there is evidence in the literature that changes in mechanochemical transduction occur with age, it is also possible that changes in mechanophysiology promote aging. Considering that mechanical forces play an important role during development, it is likely that they also play a role in aging.
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MECHANOPHYSIOLOGY OF VERTEBRATES AFFECTS TISSUE FORMATION
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Mechanical loading and responses to mechanical loading play a central role in development and evolution of a variety of species as well as in the mechanophysiology of ECMs (Refs. 32, 47). Gravitational forces acting on mammalian tissues increase the net muscle forces required for locomotion or other bodily movements (47). In addition, as body mass increases during development, musculoskeletal and other ECMs are able to adapt to the increased mechanical requirements by increasing the size of the tissue components necessary to generate force and store energy required for movement (Refs. 32, 47). The level of external force required for vertebrates to ambulate and move their limbs is related to the size of the musculoskeleton through anabolic and catabolic processes (47). Beyond the influence of gravity on catabolic and anabolic changes in the ECM, once body mass reaches an equilibrium size, alterations in the regulation of catabolic and anabolic processes that are associated with maturation must occur; these alterations may also predispose connective tissue to changes that are associated with aging and disease.
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MECHANOCHEMICAL TRANSDUCTION INVOLVES COMPONENTS OF ECM
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During evolution, mechanical and other fundamental stimuli such as light, pH, and temperature were critical environmental parameters; these parameters are sensed by cells via intracellular signal transduction pathways (29). These responses have been preserved and further developed during evolution (29). Mechanical stimuli appear to activate the same signaling pathways that are activated by hormones, growth factors, and inflammatory mediators (29, 47) (see Figs. 1 and 2), leading to the hypothesis that the synergy between these mediators may be altered during aging and repair processes (47). The intracellular events initiated by external mechanical stimuli, growth factors, growth hormones, and inflammatory mediators have been recently summarized (7, 23, 29) (see Figs. 1 and 2). They include 1) activation of cell membrane ion channels, 2) activation and Ca2+ release from intercellular gap junctions, 3) integrin-dependent activation of the phosphorelay system within the cell cytoplasm (Figs. 3 and 4), 4) activation of growth factor receptors within the cell membrane, and 5) upregulation of cell proliferation mediated through hormone receptors (see Refs. 44 and 47 for reviews). Presently, knowledge suggests that cellular metabolism is not only affected by the balance between applied external and internal mechanical forces already present in ECM (Ref. 47) but can be further modulated through levels of growth factors and hormones and their receptors, as well as by levels of inflammatory mediators and Ca2+ (15, 22, 37). A recent report suggests that mitochondrial uptake of intracellular Ca2+ may act as a control point for apoptosis (42). Because increased intracellular Ca2+ concentration is associated with mechanical stimulation of stretch receptors in the cell membrane and intercellular gap junctions, it is important to examine the possible relationship between changes in mechanochemical transduction and the changes associated with aging of ECM.
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Fig. 1. Relationship between the phosphorelay system and cell behavior. This diagram shows the relationship between stimuli external to the cell and the resulting activation of phosphorelay pathways. Phosphorelay pathways can be activated by direct membrane stretch, which is caused by osmotic, hydrostatic, electromechanical, and hydrodynamic effects; ion channel stretching; stretching of intercellular junctions (not shown); stretching of growth factor and hormone receptors; stretching of cell surface integrins; the presence of extracellular cytokines; and by combinations of these effects. In some cases, membrane stretching can activate growth factor receptors even in the absence of growth factors (ligand that normally activates the receptor). Any of these effectors can potentially activate the phosphorelay pathways shown in Fig. 2.
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Fig. 2. Diagram of activation of the phosphorelay system by physical forces. Mitogen-activated protein kinases (MAPKs) are part of a phosphorelay system, which are activated through cell membrane and cytoskeletal stretching such as diagrammed in Fig. 1. Tension applied to the extracellular matrix (ECM) occurs as a result of mechanical, osmotic, hydrostatic, fluid, and electromechanical effects, leading to stretching of the cell membrane. Cell mitosis, gene expression, and protein synthesis occur by generation of secondary messengers that activate the pathways shown. These pathways of the phosphorelay system include the extracellular signal-regulated kinase (ERK-1/2) pathway, which is part of the MAPK kinase kinase (MKKK) pathway (right), the c-Jun kinase (JNK) (JNK1, JNK2 and JNK3) pathway (middle), and the p38 pathway (left). The ERK-1/2 pathway is stimulated by growth factors, cytokines, and G protein and can lead to increased cell mitosis. The JNK pathway is stimulated by growth factors and environmental stresses, altering gene expression and controlling programmed cell death. The p38 pathway regulates protein expression of many cytokines such as interleukin-1, which has been implicated in modulating the response to mechanical loading in a number of tissues such as cartilage.
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Fig. 4. Integrin-mediated activation of mechanochemical transduction. This diagram illustrates how tension applied through collagen fibrils (top) at the ECM-cell interface leads to synthesis of new tissue via activation of MAPK phosphorelay systems. Energy transfer to the attached integrin subunits from the collagen fibril of the ECM putatively leads to physical changes in the cell cytoskeleton (actin filaments and other cytoskeletal molecules shown) that affect activation of focal adhesion kinase (FAK) and stimulation of secondary messengers. Secondary messengers activate several different pathways that are part of the phosphorelay system. This process leads to activation of MAPK, upregulation of protein synthesis and cell mitotic activity, and changes in gene expression.
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STRESSES THAT EXIST IN ECMS
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ECMs found in musculoskeletal, cardiovascular, pulmonary, and dermal tissues are all under tension under normal physiological conditions, even in the absence of external loading. The level of this tension appears to decrease with age (Refs. 44, 47). Tensional forces that are present at the collagen fibril-cell interface arise from a variety of effects, including osmotic, hydrostatic, hydrodynamic, and electromechanical forces (see Refs. 44, 47). Tension present in ECMs not only fulfills cosmetic functions, e.g., smooth skin is considered much more appealing than wrinkled skin, but it also sets up a state of dynamic mechanical loading at the collagen fibril-cell interface that stimulates mechanochemical transduction (Refs. 44, 47). At the collagen fibril-cell interface, increases in external loading result in increases in internal stresses acting on collagen fibrils. This internal tension acts to distribute external forces and effectively distribute the tissue response to increases in external loading (Refs. 44, 47).
Beyond this effect, the contractile force exerted by cells grown in collagen lattices (16) suggests that, under normal physiological conditions, tension applied by cells to the attached ECM balances the tension within collagen fibrils of the tissue. Recent evidence suggests that this tension is reduced or lost during aging and age-related diseases such as osteoarthritis (44). Changes in external mechanical loading such as decreased mechanical loading that occurs as a result of disuse (50) or mechanical overload (12) appear to lead to changes in ECM structure and function that parallel those changes seen in aging.
Application of external forces to ECMs such as skin produce responses that give us information concerning the role of tensile and compressive forces on ECM tissue metabolism (Refs. 44, 47). The use of compression dressings placed over areas of skin marked by hypertrophic scarring results in resorption of some of the underlying scar tissue (25), whereas application of tension to skin-like cell-seeded collagen matrices leads to tissue synthesis and reorganization (16). Tissue expansion, normally accomplished by using an expandable balloon placed in the dermis, applies tension to the epidermis and compression to the underlying dermal tissue. This procedure has the effect of thickening the epidermis (3, 24, 34, 36), but the dermis and subcutaneous tissue are significantly thinned (34, 36). These studies underscore that the biochemical response of cells to the application of external loads is dependent on the type of load; tension appears to support tissue anabolism, and compression leads to tissue resorption (47). However, the rate of loading, the intensity, and the number of cycles affect the cellular responses to external mechanical loading (see Refs. 44, 47, for recent reviews). Results of a recent study suggest that young cells proliferate and synthesize matrix components better than adult cells (5), suggesting that changes in cellular responses to mechanical loading may occur with age.
Although a variety of cell types found in ECMs appear to undergo mitosis and biosynthetic production of ECMs as a result of tension (Refs. 44, 47), fluid shear forces have also been reported to modulate mechanochemical transduction processes. In bone, fluid shear through channels in osteonic bone is a major factor in upregulating bone cell metabolism (4). In addition, in the vascular system, chronic increases in wall shear stress that occur as a result of increased blood pressure have been reported to lead to vascular remodeling and increased vascular wall diameter and thickness, in the body's attempt to restore normal values of vessel wall shear stress (28). Changes associated with vascular remodeling due to increased blood pressure, to a first approximation, parallel the biochemical changes associated with aging of the vessel wall (45).
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THE STRUCTURE AND COMPOSITION OF ECMS CHANGE WITH AGE
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Collagen is the most abundant protein in ECMs and forms the essential mechanical building blocks in musculoskeletal and other tissues (see, for example, Ref. 51). Although the predominant structural form of collagen is fibrillar, it is found in both fibril- and nonfibril-forming forms in mammals. The fibril-forming collagens provide the structural framework of tissues; they include types I, II, III, V, and XI collagens (51). All of the fibril-forming collagens self-assemble into cross-striated fibrils that bear tensile loads in tissues (44, 47). In addition, fibril-associated collagens with interrupted triple helical sequences (FACIT collagens), such as types IX, XI, and XII collagens, are found on the surface of collagen fibrils and may connect fibrillar collagens to other components of the ECM (51). These collagens are probably involved in load transfer within the interfibrillar matrix (44, 47).
In general, the type I collagen content of ECMs increases with age, whereas the type III collagen content is decreased (30, 31). The PG content also appears to decrease with age (41). Fragmentation of elastic tissues occurs in skin and cardiovascular tissue, and disruption and unraveling of collagen fibers occur in aged skin (20, 27). In skin, the strain at which the maximum stress occurs (36), as well as the maximum stress (47), decreases with age, consistent with the disruption of the collagen network associated with age.
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HOW DO CHANGES IN MECHANOCHEMICAL TRANSDUCTION LEAD TO AGE-RELATED CHANGES IN ECM?
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Mechanical stretching (tension) activates the phosphorelay pathways (Figs. 2, 3, 4) through either integrin-dependent or integrin-independent mechanisms. Beyond this, reduction of mechanical loading downregulates the extracellular signal-regulated kinase (ERK) pathways leading to quiescence (39). Some cells undergo apoptosis as a result of loss of mechanical loading (11, 17), which is reduced in the presence of adhesion-blocking antibodies to integrins-
1
1 and -21 (33). Integrin-dependent apoptosis from loss of mechanical loading is blocked in cells that lack 2-integrin or that undergo depolymerization of F actin (33). ERK-1/2 activation [mitogen-activated protein kinase (MAPK) pathway activation] is decreased in aged skin, suggesting that mechanochemical transduction may be downregulated with increased age (8). The downregulation may occur either at the level of the cell membrane or cell cytoskeleton or through changes in activation of secondary messengers.
Elastin peptides derived from the degradation of the vessel wall are present in serum and are associated with vessel wall aging. Elastin peptides activate phospholipase C, inducing the production of inositol trisphosphate, leading to an increase of intracellular free Ca2+ and diacylglycerol (13). This process leads to phosphorylation of members of the MAPK family (13). A progressive age-dependent uncoupling of the elastin receptor occurs that impairs transduction and alters Ca2+ signaling and results in loss in Ca2+ homeostasis in vascular smooth muscle cells (13). Mechanochemical transduction through elastin receptors also appears to act via the phosphorelay pathways and may also be impaired during aging of ECM.
Hormones and growth factors appear to interact with mechanical signals to alter the sensitivity of effector cells to mechanical load (10, 15, 26). Several authors have reported that the levels and production of hormones and growth factors decline during aging. Reduced levels of mechano-growth hormone and insulin-like growth factor I (IGF-I) have been reported to occur in bone during aging and to lead to reduced osteogenic effects to mechanical loading (15). Rousseau et al. (40) showed a decrease in IGF-I secretion and production from cultured rat chondrocytes during aging. Ribault et al. (37) reported a decrease in DNA synthesis as well as decreased epidermal growth factor binding sites and dissociation constants during aging of rat articular chondrocytes. Iqbal et al. (22) demonstrated a decrease in incorporation of 35S into equine articular cartilage proteoglycans during aging. Synthesis of proteoglycans in equine cartilage was stimulated by transforming growth factor- and downregulated by interleukin-1 and retinoic acid.
Chondrocytes show a continuous age-related decline in proliferative responses to serum and a decrease in levels of DNA synthesis in response to growth factors. Cells from young donors (10-20 yr of age) respond better to growth factors, including a platelet-derived growth factor AA chain homodimer (PDGF-AA) (18, 19). During aging, there is a profound decline in levels of DNA synthesis and cell replication in response to growth factors (18, 19).
Mechanical strain, testosterone, and estrogen all stimulate proliferation of primary cultures of male rat long bone-derived osteoblast-like cells (9). Rat osteoblast-like cells from males or females exhibit strain-related proliferation mediated through the estrogen receptor in a manner that does not compete with estrogen but can be blocked with receptor modulators (9). Decreases in testosterone and estrogen associated with aging may lead to inefficient mechanochemical transduction and changes in tissue metabolism (52, 53). Although there is evidence that mechanochemical transduction appears to be downregulated with increased age, it is also possible that mechanophysiology contributes to aging through a process commonly referred to as a "use it or lose it" phenomenon.
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MECHANOCHEMICAL TRANSDUCTION AND MECHANOPHYSIOLOGY OF ECM
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In this mini-review, we have tried to make clear that the transduction of mechanical forces has a significant impact on the development, maturation, and aging of ECMs. What is also clear is that the number of potential factors, effectors, and pathways influenced by external mechanical loading is very large and will make elucidation of the interrelationships between integrin-dependent, hormone (or hormone receptor)-dependent, Ca2+-dependent and growth factor- (or growth factor receptor-) dependent processes and mechanophysiology of ECMs an extremely interesting field of study. Of particular importance will be understanding how studies of the effects of mechanical forces on isolated cells and tissues in vitro relate to the influence of internal and external forces and stresses on cells and groups of cells in vivo. The further development of experimental and theoretical methodologies to analyze the influence of external forces on nonisotropic viscoelastic biological materials, as well as to identify what stresses are experienced at the cellular and subcellular levels, will allow us to understand transduction at both macroscopic and microscopic levels. Further study of the interactions among mechanical forces, growth factors, and hormones will give us more information to understand how changes in mechanochemical transduction processes may be associated with aging of connective tissue.
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FOOTNOTES
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Address for reprint requests and other correspondence: F. H. Silver, Dept. of Pathology and Laboratory Medicine, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854 (E-mail: silverfr{at}umdnj.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Copyright © 2003 by the American Physiological Society.
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ABSTRACT
MECHANOPHYSIOLOGY OF VERTEBRATES...
