The role of periostin in tissue remodeling across health and disease

Periostin, also termed osteoblast-specific factor 2, is a matricellular protein with known functions in osteology, tissue repair, oncology, cardiovascular and respiratory systems, and in various inflammatory settings. However, most of the research to date has been conducted in divergent and circumscribed areas meaning that the overall understanding of this intriguing molecule remains fragmented. Here, we integrate the available evidence on periostin expression, its normal role in development, and whether it plays a similar function during pathologic repair, regeneration, and disease in order to bring together the different research fields in which periostin investigations are ongoing. In spite of the seemingly disparate roles of periostin in health and disease, tissue remodeling as a response to insult/injury is emerging as a common functional denominator of this matricellular molecule. Periostin is transiently upregulated during cell fate changes, either physiologic or pathologic. Combining observations from various conditions, a common pattern of events can be suggested, including periostin localization during development, insult and injury, epithelial–mesenchymal transition, extracellular matrix restructuring, and remodeling. We propose mesenchymal remodeling as an overarching role for the matricellular protein periostin, across physiology and disease. Periostin may be seen as an important structural mediator, balancing appropriate versus inappropriate tissue adaption in response to insult/injury.     

Myosin II in mechanotransduction: master and commander of cell migration, morphogenesis, and cancer

Mechanotransduction encompasses the role of mechanical forces in controlling cell behavior by activating signal transduction pathways. Most forces at a cellular level are caused by myosin II, which contracts and cross-links actin. Myosin II-dependent forces are transmitted through the actin cytoskeleton to molecular endpoints that promote specific cellular outcomes, e.g., cell proliferation, adhesion, or migration. For example, most adhesive and migratory phenomena are mechanically linked by a molecular clutch comprised of mechanosensitive scaffolds. Myosin II activation and mechanosensitive molecular mechanisms are finely tuned and spatiotemporally integrated to coordinate morphogenetic events during development. Mechanical events dependent on myosin II also participate in tumor cell proliferation, invasion, and metastatic dissemination. Specifically, tumor cells alter the mechanical properties of the microenvironment to create favorable conditions for proliferation and/or dissemination. These observations position myosin II-dependent force generation and mechanotransduction at the crossroads between normal development and cancer.     

Non-canonical Wnt signals regulate cytoskeletal remodeling in osteoclasts

Osteoclasts are multinucleated cells responsible for bone resorption. Osteoclasts adhere to the bone surface through integrins and polarize to form actin rings, which are formed by the assembly of podosomes. The area contained within actin rings (also called sealing zones) has an acidic pH, which causes dissolution of bone minerals including hydroxyapatite and the degradation of matrix proteins including type I collagen by the protease cathepsin K. Osteoclasts resorb bone matrices while moving on bone surfaces. Osteoclasts change their cell shapes and exhibit three modes for bone resorption: motile resorbing mode for digging trenches, static resorbing mode for digging pits, and motile non-resorbing mode. Therefore, the actin cytoskeleton is actively remodeled in osteoclasts. Recent studies have revealed that many molecules, such as Rac, Cdc42, Rho, and small GTPase regulators and effectors, are involved in actin cytoskeletal remodeling during the formation of actin rings and resorption cavities on bone slices. In this review, we introduce how these molecules and non-canonical Wnt signaling regulate the bone-resorbing activity of osteoclasts.     

Regulatory mechanisms of atrial fibrotic remodeling in atrial fibrillation

Electrical, contractile and structural remodeling have been characterized in atrial fibrillation (AF), and the latter is considered to be the major contributor to AF persistence. Recent data show that interstitial fibrosis can predispose to atrial conduction impairment and AF induction. The interplay between cardiac matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of MMPs (TIMPs), is thought to be critical in atrial extracellular matrix (ECM) metabolism. At the molecular level, angiotensin II, transforming growth factor-beta1, inflammation and oxidative stress are particularly important for ECM dysregulation and atrial fibrotic remodeling in AF. Therefore, we review recent advances in the understanding of the atrial fibrotic process, the major downstream components in this remodeling process, and the expression and regulation of MMPs and TIMPs. We also describe the activation of bioactive molecules in both clinical studies and animal models to modulate MMPs and TIMPs and their effects on atrial fibrosis in AF.     

Extracellular matrix components associated with remodeling processes in brain

In the central nervous system, various extracellular matrix components have been identified which are strongly expressed during development and in most areas of the brain down-regulated during maturation. Examples are tenascin-C, neurocan and hyaluronan. While tenascin-C is well known to be associated with morphogenic events and the active contribution of hyaluronan to various physiological processes is increasingly acknowledged, neurocan belongs to a class of molecules thought to be generally more associated with barrier functions: chondroitin sulfate proteoglycans. Consideration of these and related molecules and their processing in the context of the general organization of the brain extracellular matrix, their changes during brain maturation and their implication in different types of remodeling processes in adult brain, like normal and pathological synaptic plasticity, inflammatory and dementia-associated diseases and gliomas, may indicate that components of the extracellular matrix could provide valuable early information about the pathological state of the brain.Received 29 January 2004; received after revision 25 March 2004; accepted 2 April 2004     

The role of periostin in lung fibrosis and airway remodeling

Periostin is a protein that plays a key role in development and repair within the biological matrix of the lung. As a matricellular protein that does not contribute to extracellular matrix structure, periostin interacts with other extracellular matrix proteins to regulate the composition of the matrix in the lung and other organs. In this review, we discuss the studies exploring the role of periostin to date in chronic respiratory diseases, namely asthma and idiopathic pulmonary fibrosis. Asthma is a major health problem globally affecting millions of people worldwide with significant associated morbidity and mortality. Periostin is highly expressed in the lungs of asthmatic patients, contributes to mucus secretion, airway fibrosis and remodeling and is recognized as a biomarker of Th2 high inflammation. Idiopathic pulmonary fibrosis is a fatal interstitial lung disease characterized by progressive aberrant fibrosis of the lung matrix and respiratory failure. It predominantly affects adults over 50 years of age and its incidence is increasing worldwide. Periostin is also highly expressed in the lungs of idiopathic pulmonary fibrosis patients. Serum levels of periostin may predict clinical progression in this disease and periostin promotes myofibroblast differentiation and type 1 collagen production to contribute to aberrant lung fibrosis. Studies to date suggest that periostin is a key player in several pathogenic mechanisms within the lung and may provide us with a useful biomarker of clinical progression in both asthma and idiopathic pulmonary fibrosis.     

The role of neuropeptides in adverse myocardial remodeling and heart failure

In addition to traditional neurotransmitters of the sympathetic and parasympathetic nervous systems, the heart also contains numerous neuropeptides. These neuropeptides not only modulate the effects of neurotransmitters, but also have independent effects on cardiac function. While in most cases the physiological actions of these neuropeptides are well defined, their contributions to cardiac pathology are less appreciated. Some neuropeptides are cardioprotective, some promote adverse cardiac remodeling and heart failure, and in the case of others their functions are unclear. Some have both cardioprotective and adverse effects depending on the specific cardiac pathology and progression of that pathology. In this review, we briefly describe the actions of several neuropeptides on normal cardiac physiology, before describing in more detail their role in adverse cardiac remodeling and heart failure. It is our goal to bring more focus toward understanding the contribution of neuropeptides to the pathogenesis of heart failure, and to consider them as potential therapeutic targets.     

How cardiomyocytes sense pathophysiological stresses for cardiac remodeling

In the past decades, the cardiovascular community has laid out the fundamental signaling cascades that become awry in the cardiomyocyte during the process of pathologic cardiac remodeling. These pathways are initiated at the cell membrane and work their way to the nucleus to mediate gene expression. Complexity is multiplied as the cardiomyocyte is subjected to cross talk with other cells as well as a barrage of extracellular stimuli and mechanical stresses. In this review, we summarize the signaling cascades that play key roles in cardiac function and then we proceed to describe emerging concepts of how the cardiomyocyte senses the mechanical and environmental stimuli to transition to the deleterious genetic program that defines pathologic cardiac remodeling. As a highlighting example of these processes, we illustrate the transition from a compensated hypertrophied myocardium to a decompensated failing myocardium, which is clinically manifested as decompensated heart failure.     

Neuronal signaling and the regulation of bone remodeling

An increasing number of studies suggest that nerve-derived signals play an important role in the regulation of bone remodeling. Neuropeptides and receptors/transporters of adrenergic, glutaminergic, serotoninergic, dopaminergic and sensory nature have been described in osteoblasts in vitro. Downstream signaling pathways and targets genes have been identified, but the in vivo relevance of these findings remained controversial until more recent gene gain and loss of function studies confirmed the role of CGRP and beta2-adrenergic receptor signaling in osteoblasts. Tissue and time-conditional mutant mice originally generated for studies unrelated to bone are now available tools to determine the role of neuronal signaling in bone and to dissociate the central and peripheral role of these signals. Lastly, understanding how the central nervous system integrates homeostatic signals with the regulation of bone homeostasis will be the next exciting subject of research in the field.     

Cytokine-mediated proteolysis in tissue remodelling

Summary Proteolytic enzymes play a key role in a variety of physiological processes in which the degradation of macromolecules is essential: angiogenesis, embryogenesis, bone and tissue remodelling, blood hemostasis and cell migration. The action of these enzymes is also crucial in the development of many pathological conditions such as wound healing, neoplasia, inflammation and arthritic disorders.the activity of proteases is negatively affected by specific protease-inhibitors. Various growth factors and other cytokines modulate the synthesis and secretion of both proteases and protease-inhibitors. The study of this regulation results in a better insight into (patho)physiology at the molecular level and promises to result in alternative treatment strategies.     

Cytokine-mediated proteolysis in tissue remodelling

Proteolytic enzymes play a key role in a variety of physiological processes in which the degradation of macromolecules is essential: angiogenesis, embryogenesis, bone and tissue remodelling, blood hemostasis and cell migration. The action of these enzymes is also crucial in the development of many pathological conditions such as wound healing, neoplasia, inflammation and arthritic disorders. The activity of proteases is negatively affected by specific protease-inhibitors. Various growth factors and other cytokines modulate the synthesis and secretion of both proteases and protease-inhibitors. The study of this regulation results in a better insight into (patho)physiology at the molecular level and promises to result in alternative treatment strategies.     

Catecholamine biosynthesis in vascular tissue

Zusammenfassung Die Umwandlung von Tyrosin in Katecholamin wurde in verschiedenen Blutgefässen untersucht. Die Katecholamin-Biosynthese erfolgte am schnellsten in der Arteria mesenterica sup. (0,6 g/g/h), was zehnmal höher liegt als diejenige in der Aorta oder in der Arteria pulmonalis.