Mechanobiology and Diseases of Mechanotransduction Donald E Ingber
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PLEASANT RIDGE EXHIBIT 1 71 ^ REVIEW ARTICLE ^ Mechanobiology and diseases of mechanotransduction Donald E Ingber The current focus of medicine on molecular genetics ignores Introduction the physical basis of disease even though many of the problems that lead to pain and morbidity, and bring patients The molecular biology revolution has led to advances to the doctor's of®ce, result from changes in tissue structure in knowledge and new technologies that are revolu- or mechanics. The main goal of this article is therefore to tionizing the way in which clinical medicine is help integrate mechanics into our understanding of the practiced. Completion of the Human Genome Pro- molecular basis of disease. This article ®rst reviews the key ject,massively parallel gene and protein pro®ling roles that physical forces, extracellular matrix and cell techniques,and powerful bioinformatics tools are just structure play in the control of normal development, as well a few examples. Yet there is a huge disconnect as in the maintenance of tissue form and function. Recent between these `genome-age' technologies and the insights into cellular mechanotransduction Ð the molecular reality of how diseases manifest themselves. From mechanism by which cells sense and respond to mechanical the time the ®rst human looked,listened and felt for stress Ð also are described. Re-evaluation of human what is wrong with a sick friend,caregivers have pathophysiology in this context reveals that a wide range recognized the undeniable physical basis of disease. of diseases included within virtually all ®elds of medicine The thrill in the chest of a patient with aortic valve and surgery share a common feature:their etiology or disease,bounding pulse in the hypertensive and clinical presentation results from abnormal mechanotrans- wheeze of the patient with emphysema all ignite duction. This process may be altered by changes in cell re¯exive clinical responses in the mind of the skilled mechanics, variations in extracellular matrix structure, or by physician,and sometimes even lead to immediate deregulation of the molecular mechanisms by which cells diagnoses. sense mechanical signals and convert them into a chemical But in the current genome euphoria,there appears or electrical response. Molecules that mediate mechano- to be no place for `physicality'. This is especially transduction, including extracellular matrix molecules, worrisome given that abnormal cell and tissue transmembrane integrin receptors, cytoskeletal structures responses to mechanical stress contribute to the and associated signal transduction components, may there- etiology and clinical presentation of many important fore represent targets for therapeutic intervention in a diseases,including asthma,osteoporosis,athero- variety of diseases. Insights into the mechanical basis of sclerosis,diabetes,stroke and heart failure. There is tissue regulation also may lead to development of improved also a strong mechanical basis for many generalized medical devices, engineered tissues, and biologically- medical disabilities,such as lower back pain and inspired materials for tissue repair and reconstruction. irritable bowel syndrome,which are responsible for a major share of healthcare costs world-wide. In fact, Keywords: cytoskeleton; disease; extracellular matrix; integrin; mechanical surgeons sometimes even use mechanical forces as forces; mechanotransduction; stress-activated ion channels; tissue engineering therapeutics,such as when traction forces are used to Ann Med 2003; 35: 1±14 accelerate bone healing. However,what is missing is how these physical interventions could in¯uence cell and tissue function,or how altered cell or tissue From the Vascular Biology Program,Departments of Surgery mechanics may contribute to disease development. and Pathology,Children's Hospital and Harvard Medical School, In this article,I ®rst review the fundamental role Boston,MA 02115,USA. that physical forces and changes in tissue mechanics Correspondence: Donald E Ingber,MD,PhD,Children's Hospital,Enders 1007,300 Longwood Avenue,Boston,MA play in normal development and physiology. I then 02115,USA. Fax: 617-232-7914. E-mail: donald.ingber@tch. describe recent advances in our understanding of harvard.edu cellular mechanotransduction,the molecular mech- # 2003 Taylor & Francis. ISSN 0785-3890 DOI 10.1080/07853890310016333 Annals of Medicine 35 T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF} N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:38:57 Page Count:14 Page Range:1±14 Page:1 2INGBER Abbreviations and acronyms Key messages . ECM extracellular matrix Mechanical forces are critical regulators of ICAM intercellualr adhesion molecule cellular biochemistry and gene expression as PDGF platelet-derived growth factor well as tissue development. RGD argine-glycine-aspartate . Mechanotransduction Ð the process by which 3D three-dimensional cells sense and respond to mechanical signals Ð is mediated by extracellular matrix, transmem- brane integrin receptors, cytoskeletal structures anism by which cells sense and respond to mechanical and associated signaling molecules. signals. Finally,I explain how the clinical manifesta- . Many ostensibly unrelated diseases share the tions of many ostensibly unrelated diseases similarly common feature that their etiology or clinical result from abnormal mechanotransduction,and how this insight may lead to new avenues for therapeutic presentation results from abnormal mechano- intervention. transduction. Mechanotransduction may be altered through changes in cell mechanics, extracellular matrix structure or by deregulation of the molecular mechanisms by which cells Mechanobiology sense mechanical signals or convert them into a chemical response. In biology and medicine,we tend to focus on the . Molecules that mediate mechanotransduction importance of genes and chemical factors for control may represent future targets for therapeutic of tissue physiology and the development of disease, whereas we commonly ignore physical factors. This is intervention in a variety of diseases. Insights interesting because it was common knowledge at the into the mechanical basis of tissue regulation turn of the last century that mechanical forces are also may lead to development of improved critical regulators in biology (1). Wolff's law describ- medical devices, engineered tissues, and biomi- ing that bone remodels along lines of stress was metic materials for tissue repair and reconstruc- published in 1892 (2). However,the advent of more tion. reductionist approaches in the basic sciences,and the demonstration of their power to advance under- standing of the molecular basis of disease,led to a loss of interest in mechanics. example,are composed of several organs (e.g.,bone, Although it has received much less attention than muscle) that are constructed by combining various the genomics revolution,there has been a renaissance tissues (e.g.,bone,muscle,connective tissue,vascular in the ®eld of mechanobiology over the past two endothelium,nerve). These tissues,in turn,are decades. Physiologists and clinicians now recognize composed of groups of living cells held together by the importance of mechanical forces for the develop- an extracellular matrix (ECM) comprised of a net- ment and function of the heart and lung,the growth work of collagens,glycoproteins,and proteoglycans. of skin and muscle,the maintenance of cartilage and Each cell contains a surface membrane,intracellular bone,and the etiology of many debilitating diseases. organelles,a nucleus,and a ®lamentous cytoskeleton Exploration of basic mechanisms of sensation and that connects all these elements and is permeated by a autonomic control,including hearing,balance,touch, viscous cytosol. Each of these subcellular components and peristalsis,also has demanded explanation in is,in turn,composed of clusters of different mol- mechanical terms. At the same time,biologists have ecules. In other words,our bodies are complex come to recognize that mechanical forces serve as hierarchical structures,and hence mechanical defor- important regulators at the cell and molecular levels, mation of whole tissues results in coordinated and that they are equally potent as chemical cues. For structural rearrangements on many different size example,cell-generated tensional forces have been scales. shown to regulate diverse functions,ranging from To understand how individual cells experience chromosome movements and cell proliferation to mechanical forces,we therefore must ®rst identify tissue morphogenesis,in addition to cell contractility the path by which these stresses are transmitted and motility (3±5). through tissues and across the cell surface. As in any To explain mechanoregulation,we must take into three-dimensional (3D) structure,mechanical loads account that living organisms,such as man,are will be transmitted across structural elements that are constructed from tiers of systems within systems physically interconnected. Thus,forces that are within systems (4,6,7). Our arms and legs, for applied to the entire organism (e.g.,due to gravity # 2003 Taylor & Francis. ISSN 0785-3890 Annals of Medicine 35 T&F -:- FULL SGML TEXT -:- Annals of Medicine MS. 149 Op. PGW {F2-PDF} N:/SANN/149/149.3D Produced: 24/07/2003 At: 14:39:21 Page Count:14 Page Range:1±14 Page:2 DISEASES OF MECHANOTRANSDUCTION 3 or movement) or to individual tissues would be integrins that link to the internal cytoskeleton provide distributed to individual cells via their adhesions