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Mechanostasis in Apoptosis and Medicine Progress in Biophysics and Molecular Biology 106 (2011) 517e524 Contents lists available at ScienceDirect Progress in Biophysics and Molecular Biology journal homepage: www.elsevier.com/locate/pbiomolbio Review Mechanostasis in apoptosis and medicine D.D. Chan a,1, W.S. Van Dyke a, M. Bahls b, S.D. Connell a, P. Critser a, J.E. Kelleher c, M.A. Kramer a, S.M. Pearce a, S. Sharma a, C.P. Neu a,* a Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, United States b Department of Health and Kinesiology, Purdue University, West Lafayette, IN 47907, United States c School of Mechanical Engineering, Purdue University, West Lafayette, IN 47907, United States article info abstract Article history: Mechanostasis describes a complex and dynamic process where cells maintain equilibrium in response Available online 8 August 2011 to mechanical forces. Normal physiological loading modes and magnitudes contribute to cell prolifera- tion, tissue growth, differentiation and development. However, cell responses to abnormal forces include Keywords: compensatory apoptotic mechanisms that may contribute to the development of tissue disease and Apoptosis pathological conditions. Mechanotransduction mechanisms tightly regulate the cell response through Programmed cell death discrete signaling pathways. Here, we provide an overview of links between pro- and anti-apoptotic Mechanobiology signaling and mechanotransduction signaling pathways, and identify potential clinical applications for Shear stress/strain Mechanotransduction treatments of disease by exploiting mechanically-linked apoptotic pathways. Ó Homeostasis 2011 Elsevier Ltd. All rights reserved. Contents 1. Introduction . .................................................517 2. Mechanostasis: tissues adapt to physical cues . ....................................518 3. Programmed cell death . .................................................519 4. Mechanotransduction and apoptosis . ............................................519 4.1. Extrinsic pathway . .......................519 4.2. Intrinsic pathway . .......................520 4.3. Caspase-independent cell death . .......................521 4.4. Apoptotic pathway crosstalk . .......................522 5. Mechanomedicine and apoptosis . ........................................... 522 6. Outlook .......................................................................... ................................................ 522 Conflict of interest . .......................523 Acknowledgments . .......................523 References................................................................. ................................ .......................523 1. Introduction Apoptosis, a programmed cell death mechanism, is characterized by nuclear chromatin condensation, cytoplasmic vacuole forma- A paradox of morphogenesis is that programmed cell death is tion, and plasma membrane blebbing (Kresch et al., 1998). As the vital for the growth and maintenance of the living adult form. embryo matures, cells are removed by apoptosis to form joints and digitated appendices (Kimura and Shiota, 1996), to create airway branching for maximum surface area and gas exchange (Kresch et al., 1998), and to develop cardiac electrophysiology conduction * Corresponding author. Tel.: þ1 765 496 1426; fax: þ1 765 494 0902. systems (Poelmann and Gittenberger-de Groot, 1999). In postnatal E-mail address: [email protected] (C.P. Neu). organisms, a combination of mitosis and apoptosis maintains cell 1 First authorship was determined by a haiku writing competition that was judged by three unbiased faculty members. The winning haiku was: “Sensing numbers with a turnover of approximately a hundred thousand outside force,/a cell shifts toward life or death./But which path to take?”. cells each second (Vaux and Korsmeyer, 1999). Apoptosis is integral 0079-6107/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.pbiomolbio.2011.08.002 518 D.D. Chan et al. / Progress in Biophysics and Molecular Biology 106 (2011) 517e524 in the remodeling of many tissues including skin wound healing, strains do not exceed a minimum effective strain (Fig. 1). If local lung remodeling, and bone repair (Greenhalgh, 1998; Polunovsky strains exceed the minimum, modeling changes the bone structure et al., 1993; Manolagas, 2000). and attenuates strain magnitudes. The humeri of professional Despite the physiological importance of apoptosis, numerous tennis players represent one classic example, where radiographs diseases are linked to both innate and dysfunctional apoptotic reveal 30% thicker bone structures in the dominant arm due to mechanisms (VanEpps and Vorp, 2007; Clarke et al., 2008; intense and local mechanical effects (Jones et al., 1977). Hammerschmidt et al., 2007; Mattson, 2000). Mechanical ventila- More generally, mechanostasis occurs with tissue remodeling in tion can aggravate an acute lung injury through over-distension, response to mechanical force in a broad variety of tissues and over breaking down the alveolar-capillary barrier and increasing alve- hierarchical scales. For example, application of mechanical forces to olar epithelial cell apoptosis (Hammerschmidt et al., 2007). Apoptosis a healing wound alters mechanostasis and induces hypertrophic in vascular smooth muscle and endothelial cells can accelerate scars (Aarabi et al., 2007). Moreover, cells upregulate collagen atherosclerosis and other heart diseases, promoting plaque calcifi- synthesis to reinforce the extracellular matrix when they are sub- cation and increasing the size of the necrotic core (VanEpps and Vorp, jected to mechanical loads such as stretch and compression (Wang 2007; Clarke et al., 2008). Premature apoptosis of neurons charac- and Thampatty, 2006). Interestingly, remodeling is not limited to terizes numerous neurodegenerative disorders, including Parkin- forces approaching supra-physiological levels, but also occurs son’s, Huntington’s, and Alzheimer’sdiseases(Mattson, 2000). during subphysiological loading. Microgravity results in cytoskel- Cancer is linked to dysfunctional apoptotic mechanisms, where etal reorganization by decreasing the amount of actin fibers in tumor growth is due in part to suppressed apoptosis of a neoplastic vascular endothelial and glial cells (Carlsson et al., 2003; Uva et al., cell (Jaalouk and Lammerding, 2009). 2002), and is reversible upon reintroduction of gravitational effects. Mechanical homeostasis is a key determinant of cellular Programmed cell death serves as one potential mechanism for apoptosis. Homeostasis describes the tendency of a cell, tissue, or maintaining mechanostasis (Fig. 2). Fibroblasts, which are accus- organism to maintain equilibrium through complex and dynamic tomed to stretching, undergo apoptosis when their embedding control and feedback. Mechanical homeostasis, herein termed matrix is unloaded and tension is released (Grinnell et al., 1999). mechanostasis, is maintained in cells and tissues exposed to normal Endothelial cells are protected from apoptosis when experiencing physiological loading modes and magnitudes. The standard fluid flow induced shear stress (Kaiser et al., 1997; Dimmeler et al., example for mechanostasis is found in the bone literature, where 1996). Excessive forces can trigger apoptosis, such as chronic a simplistic model demonstrates that additional loading causes compression of chondrocytes (Loening et al., 2000) and excessive bone formation, while disuse causes bone resorption (Skerry, 2008). stretching of pulmonary endothelial cells (Birukov et al., 2003). Similarly, in the vasculature, experiments evaluating varying Severe unloading, such as in microgravity, often also shows an quantities of blood pressure, flow patterns, and vessel extension increased rate of apoptosis that is independent of cell phenotype show that arteries seek to maintain a constant mechanical state (Uva et al., 2002; Grimm et al., 2002). However, rare instances exist (Humphrey, 2008). Importantly, cell and tissue responses to where simulated microgravity leads to cell proliferation, specifi- abnormal forces include compensatory mechanisms such as cally in endothelial cells (Carlsson et al., 2003), although the effects apoptosis (Hsieh and Nguyen, 2005; Weyts et al., 2003; Haga et al., of fluid shear stress may compound these findings. Regardless, 2007; Shyu, 2009). Therefore, understanding underlying mecha- deviations from typical mechanical forces alter mechanostasis, notransduction mechanisms in the context of apoptosis may guide causing cell death through signaling pathway cascades. specific and targeted therapeutic strategies to restore mechano- Additionally, apoptosis depends on the type, composition, and stasis and mitigate diseases linked to apoptosis (Reed, 2002). rigidity of the extracellular matrix. Fibroblast apoptosis was only In this review, we discuss how mechanical forces regulate tissue mechanostasis and programmed cell death. We discuss a generalized “mechanostat” theory, first proposed by Harold Frost for bone adaptation (Frost,1987), to explore connections between a minimum effective strain and feedback for tissue adaptation by apoptosis. Further, we discuss detailed links between pro- and anti-apoptotic signaling and mechanotransduction signaling pathways. Finally, this review suggests promising future clinical applications for treatments of disease by exploiting mechanically-linked apoptotic pathways. 2. Mechanostasis: tissues adapt to physical cues Homeostasis in the biological context
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