{"title":"10. Bone Mineralization","authors":"L. Bonewald, S. Dallas, J. Gorski","doi":"10.1101/087969825.53.277","DOIUrl":"https://doi.org/10.1101/087969825.53.277","url":null,"abstract":"The mechanisms by which mineralized tissues such as bone acquire and regulate their mineral component are complex. The process of mineralization can be divided into the establishment of a primed, mineralizable matrix in which de novo mineral nucleation can occur, followed by the growth, expansion, and maturation of crystals. Perturbations in any of these events can result in bone disease and fragility. Elucidating the cellular and molecular mechanisms has been difficult because biomineralization is a combination of a physico-chemical process and a biological one. For example, phosphate participates directly in the formation of the hydroxyapatite crystals but recent studies have shown that phosphate can also directly regulate gene expression. This chapter summarizes current opinion within the field on key issues related to mineralization, such as whether mineralization is an active (cell-mediated) or a passive (physico-chemical) process and the role of cell-derived organelles/vesicles in mineralization. The molecular mediators and regulators of mineralization are reviewed and the question of whether there are unique mechanisms of mineralization in different types of bone tissue is addressed. Even though bone mineral density is currently the standard for predicting bone fragility, it is important to not only understand the inorganic component of bone, but also the organic component, as individuals with similar bone densities can have different susceptibility to fracture. These less clear properties of the skeleton that contribute to bone strength remain the focus of much investigation. THE CELLS RESPONSIBLE FOR BONE FORMATION AND MINERALIZATION Cells in the osteoblast/osteocyte lineage are responsible for bone formation...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"60 1","pages":"277-295"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83727233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"1 Evolutionary Origin of Bone and Cartilage in Vertebrates","authors":"Kinya G. Ota, S. Kuratani","doi":"10.1101/087969825.53.1","DOIUrl":"https://doi.org/10.1101/087969825.53.1","url":null,"abstract":"Most living vertebrates are characterized by possession of bones and cartilage as major components of the skeletal system, and the origin and evolution of these tissues remain intriguing questions. Classically, Geoffroy Saint-Hilaire (1818) tried to compare arthropods and vertebrates by two types of “inversions.” One is the dorsoventral inversion that brings the ventral nervous system of arthropods to the dorsal side, as seen in vertebrates. The other is the inside-out inversion to transform the arthropod exoskeleton into the vertebrate-type endoskeleton. However, it is misleading to regard the endoskeleton as the major skeleton in vertebrates. Compared with the exoskeleton in arthropods, vertebrates also have exoskeletal elements. Thus, the vertebrate exoskeleton has been compared directly with that of arthropods, as suggested by Patten (1912), Gaskell (1908), and others. However, those ideas have now been refuted by new evidence of phylogenetic relationships among animal phyla, by improved knowledge of skeletal histology and cytology, and by molecular developmental evidence for skeletogenesis. In the modern evolutionary scenario, which is largely based on phylogenetic trees constructed on molecular sequence data, it is generally accepted that vertebrates belong to the deuterostomes together with echinoderms, hemichordates, urochordates, and cephalochordates (amphioxus). This comprises a sister group to the protostomes, consisting of lophotrochozoans and ecdysozoans (Aguinaldo et al. 1997). It is along this phylogenetic tree that the origins of the vertebrate skeleton should be sought, by integrating the fossil evidence (Halstead 1974; Donoghue and Sansom 2002; Hall 2005). Comparative analyses of skeletal development in various living organisms will help guide...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"73 1","pages":"1-18"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73420155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Preface/Front Matter","authors":"O. Pourquié","doi":"10.1101/087969825.53.I","DOIUrl":"https://doi.org/10.1101/087969825.53.I","url":null,"abstract":"Our understanding of skeletal biology has taken tremendous strides during the past few years. On the one hand, the spectacular recent breakthroughs in developmental biology have led to an understanding of the global rules shaping and positioning the cartilage and bone primordia in the vertebrate embryo. On the other hand, the discovery of key master regulators of the chondrocyte and bone lineage, such as Sox9 and Runx2, as well as the signaling pathways involved in the regulation of the differentiation of these lineages, has provided a much better understanding of these processes. This knowledge led to the elucidation of the molecular etiology of a majority of bone and cartilage genetic diseases. The goal of this book is to provide a comprehensive and up-to-date summary of the field of skeletal biology. This is a large field and due to space limitations, some areas might be covered more extensively than others. However, an attempt was made to cover all stages of skeletal development and patterning, as well as differentiation of cartilage and bone cells. The complex area of bone physiology is discussed in some of the chapters, but is not addressed extensively. This book covers essentially three major themes. The first theme relates to the development and patterning of bone in vertebrates. Several chapters deal with classical model systems that have been used to study bone and cartilage patterning in the vertebrate embryo. Specifically, the limb bud and the rules governing the formation of bone primordia are addressed, as well as the","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"106 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78253028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Preface/Front Matter","authors":"L. Guarente, L. Partridge, D. Wallace","doi":"10.1101/087969824.51.i","DOIUrl":"https://doi.org/10.1101/087969824.51.i","url":null,"abstract":"The past decade or so has witnessed an explosion in knowledge about the molecular basis of the aging process and its modulation by genes and diet. This book was designed to capture the field of aging research at this exciting moment in its history. The chapters were chosen to represent many of the important threads that are woven together to provide the current framework of our understanding of aging, at the level of molecules, cells, tissues, and the whole organism. One group of chapters focuses on the model organisms that have been used to dissect the genetics and molecular biology of aging in recent years. These include yeast, C. elegans, Drosophila , and mice. The strengths and weaknesses of each system are on display, and the major findings that have emerged are described in detail. Several of the pathways identified show evolutionary conservation among these model systems, and are hence candidates for modulation of human aging. The roles of stress resistance and of DNA repair are discussed, as are genomic systems and population genetic approaches currently used to investigate aging in model organisms and humans. Human aging may have unique features that are not shared by the model organisms, and this is also addressed. Another theme in this book is the interaction between diet, metabolism, and life span. It has been known for about 75 years that a low calorie diet, termed calorie restriction or CR, can extend lifespan in rodents and in an expanding range of organisms, and these physiological","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76591231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"14 The Balance of Trophic Support and Cell Death in Adult Neurogenesis","authors":"H. Kuhn","doi":"10.1101/087969784.52.283","DOIUrl":"https://doi.org/10.1101/087969784.52.283","url":null,"abstract":"The fact that continuous proliferation of stem cells and progenitors, as well as the production of neurons, occurs in the adult CNS raises several basic questions concerning the number of neurons required in a particular system: Can we observe a continued growth of brain regions that sustain neurogenesis? Or does an elimination mechanism exist that keeps the number of cells constant? If so, are the old ones replaced or are the new neurons competing for limited network access? What signals would support their survival and integration and what factors are responsible for their elimination? This chapter addresses these and other questions regarding regulatory mechanisms affecting adult neurogenesis by controlling cell survival. ARE NEUROGENIC BRAIN REGIONS EXPANDING DESPITE SPACE LIMITATIONS? This question was initially addressed several decades ago, following the first evidence that adult mammalian neurogenesis exists. Total neuronal cell counts of the olfactory bulb (OB) and dentate gyrus (DG) at different ages revealed that in both regions, a continued growth of the granule cell layer occurs throughout adult life. From 1 month of age, when the developmental production of granule cells can be considered complete, until 1 year of age, the number of DG granule cells doubles in the rat (Bayer 1982; Bayer et al. 1982). A rise in total volume and increased cell density due to reduced cell diameter both contribute to this phenomenon. In the rat OB, a linear growth of the granule cell layer was observed with age (Kaplan et al. 1985), with the number of olfactory...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"649 1","pages":"283-298"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76270487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"5 The Use of Reporter Mouse Lines to Study Adult Neurogenesis","authors":"G. Enikolopov, Linda Overstreet-Wadiche","doi":"10.1101/087969784.52.81","DOIUrl":"https://doi.org/10.1101/087969784.52.81","url":null,"abstract":"A long-standing problem in the field of adult neurogenesis has been the need to identify newborn neurons and their precursors within a much larger population of preexisting mature neurons and glia. If these nascent cells could be identified, it would be possible to visualize and enumerate such cells in vivo, to access them for electrophysiological and molecular studies, to identify their connections in the neuronal networks, and to alter their activity and function. Several strategies have been developed to solve this problem of finding the proverbial needle in a haystack. Methods such as labeling with thymidine analogs, phenotypic analysis based on the expression of developmental markers, and retro- and lentiviral labeling have each had an important role in advancing our understanding of the proliferation and maturation of newborn neurons in the adult brain. As with all methods, these techniques have advantages and limits that demarcate their appropriate application. In this review, we focus on genetic approaches to studying adult mammalian neurogenesis, describing reporter lines of transgenic mice and summarizing recent advances that employ these emerging technologies. The general strategy of these genetic approaches is to drive the expression of “live” markers such as green fluorescent protein (GFP) in a defined population of neurons, neuronal progenitors, or stem cells. Cytoplasmic expression of fluorescent proteins (FPs) allows the full morphology of labeled cells to be visualized, whereas nuclear expression of such proteins facilitates cell enumeration. FP expression also allows labeled cells to be identified and accessed in live animals and in acute...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"13 1","pages":"81-100"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79720077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Sedivy, U. Muñoz-Najar, Jessie C. Jeyapalan, J. Campisi
{"title":"8 Cellular Senescence: A Link between Tumor Suppression and Organismal Aging?","authors":"J. Sedivy, U. Muñoz-Najar, Jessie C. Jeyapalan, J. Campisi","doi":"10.1101/087969824.51.185","DOIUrl":"https://doi.org/10.1101/087969824.51.185","url":null,"abstract":"The aging of organisms occurs at virtually every level of complexity—from molecules to tissues to organ systems. Between these extremes are the basic units of life: individual cells. Among multicellular organisms, how do cells age? The deterioration of life processes in postmitotic cells—chronological aging—is explored elsewhere in this book. Here, we consider the aging of cells that retain the capacity for proliferation in adult organisms. Normal somatic cells of higher metazoans, with the exception of germ cells and some stem cells, have a limited proliferative capacity (also referred to as replicative life span). This phenomenon was first formally described by Hayflick and Moorhead (1961), who observed that human fibroblasts, upon explant into cell culture, displayed an initial phase of rapid proliferation followed by a period of declining replicative potential. Eventually, all cells in the culture ceased dividing, but they remained in a viable and stable state. This postmitotic growth arrest was termed replicative senescence (Hayflick 1965) and, later, cellular aging. The discovery of replicative senescence led to two important hypotheses. The first one proposed that cellular senescence recapitulates aspects of organismal aging and contributes to aging phenotypes in vivo (Hayflick 1985). Although there is mounting evidence to support this idea, it still rests largely on circumstantial evidence. The second hypothesis invoked cellular senescence as a mechanism that suppresses the development of cancer (Sager 1991). There is now substantial evidence to support this hypothesis (Campisi 2005; Hemann and Narita 2007). This chapter focuses on the links among cellular...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"12 1","pages":"185-214"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86695949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stephen H. Schilling, A. Hjelmeland, J. Rich, Xiao-Fan Wang
{"title":"3 TGF-β: A Multipotential Cytokine","authors":"Stephen H. Schilling, A. Hjelmeland, J. Rich, Xiao-Fan Wang","doi":"10.1101/087969752.50.45","DOIUrl":"https://doi.org/10.1101/087969752.50.45","url":null,"abstract":"Transforming growth factor-β (TGF-β) has been implicated as an important regulator of almost all major cell behaviors and activities, including proliferation, adhesion, motility, apoptosis, and differentiation. Which of these are affected and how they are regulated in response to TGF-β depend entirely on the cell type and the context in which the TGF-β signals are received. With such a large and diverse set of biological effects in such a wide range of cell types, it is not surprising that layers of regulation and cross-talk impinge on the TGF-β signaling pathway. This chapter provides a basic introduction to the molecular and biological responses controlled by TGF-β and how different levels of input help to regulate the specificity of these responses. Subsequent chapters discuss in greater depth the signaling mechanisms and different aspects of the cellular responses to TGF-β and TGF-β family proteins. TGF-β SIGNALS MEDIATE CHANGES IN GENE EXPRESSION To elicit gene expression responses, TGF-β uses a well-characterized signal transduction pathway that extends from the cell membrane to the nucleus (see Chapter 6). This signaling cascade is initiated when active TGF-β ligand binds to the TGF-β type II receptor (TβRII), which then forms a complex with the TGF-β type I receptor, known as TβRI or activin receptor–like kinase-5 (ALK-5). Formation of this activated ligand-bound receptor complex results in the phosphorylation of TβRI/ALK-5 by TβRII, thereby activating the type I receptor and permitting binding of Smad2 and/or Smad3. These receptor-activated Smads (R-Smads) are subsequently directly phosphorylated by TβRI/ALK-5 at the carboxyl...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"23 1","pages":"45-77"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91312729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"7 TGF-β Bioavailability: Latency, Targeting, and Activation","authors":"B. Dabovic, D. Rifkin","doi":"10.1101/087969752.50.179","DOIUrl":"https://doi.org/10.1101/087969752.50.179","url":null,"abstract":"In the past decade, it has become apparent that cytokines and growth factors rely on a variety of mechanisms to regulate their activities in the extracellular milieu after secretion and before interaction with their cognate receptors (Flaumenhaft and Rifkin 1992; Saharinen et al. 1999). These mechanisms are both restrictive and protective, and they ensure that the signaling molecules attain proper concentration for receptor binding and are localized to the proper site. In this regard, TGF-β is released in a latent state in which its biological activity must be unmasked before the cytokine binds to its receptors. In this chapter, we consider the latent forms of TGF-β, the known mechanisms of activation, and the consequences of releasing TGF-β as a latent molecule. TGF-β STRUCTURE AND BIOSYNTHESIS TGF-β Structure TGF-β was originally isolated from several tissues as a 25-kD homodimer (Frolik et al. 1983; Roberts et al. 1983). Interestingly, the reports about TGF-β produced by normal cultured cells indicated that the bioactivity was detected only after treatment of the culture medium by extremes of pH (Branum et al. 1984; Pircher et al. 1984; Lawrence et al. 1985). This result was in contrast to the description of the purification of active TGF-β from tissues (Frolik et al. 1983; Roberts et al. 1983) and led to the idea that TGF-β was released complexed to a binding or masking protein. Subsequent experiments from several laboratories validated this hypothesis (Gentry et al. 1987; Gentry and Nash 1990) and showed that TGF-β is processed from a larger...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"41 1","pages":"179-202"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89882360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"2 Sirtuins: A Universal Link between NAD, Metabolism, and Aging","authors":"S. Imai, L. Guarente","doi":"10.1101/087969824.51.39","DOIUrl":"https://doi.org/10.1101/087969824.51.39","url":null,"abstract":"Nature is an endless combination and repetition of a very few laws. She hums the old well-known air through innumerable variations. Ralph Waldo Emerson Essay I History , Essays: First Series, 1841 For the past several years, Sir2 family proteins, now called “sirtuins,” have been emerging as an evolutionarily conserved, critical regulator for aging and longevity in diverse model organisms, providing a novel paradigm to the field of aging research. The SIR2 gene was originally identified by Klar et al. (1979) as one of the genes that regulate the a and α mating types of budding yeast, Saccharomyces cerevisiae . Subsequent studies have demonstrated that Sir2 has a critical role in the regulation of transcriptional silencing at mating-type loci, telomeres, and ribosomal DNA (rDNA) repeats (Guarente 1999). At mating-type loci and telomeres, the Sir complex that includes Sir2 and the other two Sir proteins, Sir3 and Sir4, forms polymerized, closed chromatin structure, namely, heterochromatin, and silences reporter genes inserted into these genomic loci (Rine and Herskowitz 1987; Gottschling et al. 1990). At rDNA repeats, Sir2 is included in another complex named RENT ( re gulator of n ucleolar silencing and t elophase exit), along with Net1, Cdc14, and other proteins, and is involved in silencing transcription of pol II reporter genes inserted into rDNA repeats (Bryk et al. 1997; Smith and Boeke 1997; Straight et al. 1999). Sir2-mediated rDNA silencing is also important for suppression of homologous recombination within this highly repetitive rDNA region (Gottlieb and Esposito 1989). Silencing requires specific lysines in the amino-terminal tails...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"26 1","pages":"39-72"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78457707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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