Osteopenic mice: animal models of the aging skeleton

While our understanding of the developmental biology of the skeleton, like that of virtually every other subject in biology, has been transformed by recent advances in human and mouse genetics, we still know very little, in molecular and genetic terms, about skeletal physiology. Thus, among the many questions that are largely unexplained are the following: why is osteoporosis mainly a women's disease? How is bone mass maintained nearly constant between the end of puberty and the arrest of gonadal functions? Molecular genetics has emerged as a powerful tool to study previously unexplored aspects of the physiology of the skeleton. Among mammals, mice are the most promising animals for this experimental work. This has been previously demonstrated e.g. through the tremendous impact of the different osteopetrotic models on our molecular understanding of osteoclastic bone resorption. Until recently the only way of studying bone loss situations and osteoporosis in mice was by using ovariectomy with all its limitations. Today, however, we have access to more sophisticated osteoporotic mouse-models from four different origins: Transgenic mice (HSV-TK), knock-out mice (OPG), inbred-strains (SAMP6), and through physiological modulation (icv application). These new models have already taught us several important lessons. The first is, that bone remodeling is more than just an autocrine/paracrine process. Multiple experimental evidence has demonstrated that the latter regulation exists, but genetics prove that there is no functional cross-control between resorption and formation. The second lesson is, that remodeling is, at least in part, subject to central regulation. Thus, osteoporosis is partly a central or hypothalamic disease. However, the most dramatic change and the most important advantage we feel is, that today we have models to test a new hypothesis regarding the etiology of osteoporosis before it turns to dogma. Taken together, mouse-studies may lead to a shift in our physiological understanding of skeleton biology and to the emergence of novel paradigms. These, in turn, should help us to devise new treatments for degenerative diseases of the skeleton such as osteoporosis and its associated clinical problems.     

Progress in osteoporosis and fracture prevention: focus on postmenopausal women

In the past decade, we have witnessed a revolution in osteoporosis diagnosis and therapeutics. This includes enhanced understanding of basic bone biology, recognizing the severe consequences of fractures in terms of morbidity and short-term re-fracture and mortality risk and case finding based on clinical risks, bone mineral density, new imaging approaches, and contributors to secondary osteoporosis. Medical interventions that reduce fracture risk include sufficient calcium and vitamin D together with a wide spectrum of drug therapies (with antiresorptive, anabolic, or mixed effects). Emerging therapeutic options that target molecules of bone metabolism indicate that the next decade should offer even greater promise for further improving our diagnostic and treatment approaches.     

Osteoimmunology: The correlation between osteoclasts and the Th17/Treg balance in osteoporosis

Osteoporosis is a bone disease that is caused by disorder of the skeletal microenvironment, and it characterized by a high disability rate and the occurrence of low energy fractures. Studies on osteoporosis and related treatment options have always been hot spots in the field of bone biology. In the past, the understanding of osteoporosis has been rather limited; research has only shown that osteoporosis involves the imbalance of bone resorption and bone formation, and recent studies have not provided cutting‐edge theories of the basic understanding of osteoporosis. Recent studies have shown crosstalk between bone and immune responses. RANKL, an essential factor for osteoclasts (OCs), is associated with the immune system. T helper (Th17)/regulatory T (Treg) cells are two different kinds of T cells that can self‐interact and regulate the differentiation and formation of OCs. Therefore, understanding the correlation between the skeletal and immune systems and further revealing the roles and the cooperation between RANKL and the Th17/Treg balance will help to provide new insights for the treatment of osteoporosis.     

Bone defects: Molecular and cellular therapeutic targets

Bone defects are one of the most serious pathologies that need tissue regeneration therapies. Studies on mesenchymal stem cells are changing the way we treat bone diseases. MSCs have been used for the treatment of osteogenesis imperfecta, hypophosphatasia, osteonecrosis of the femoral head, osteoporosis, rheumatoid arthritis and osteoarthritis. In this context, it is becoming ever more clear that the future of therapies will be based on the use of stem cells. In this concise review, we highlight the importance of the use of MSCs in bone diseases, focusing on the role of histone deacetylases and Wnt pathways involved in osteogenesis. A better understanding of MSC biology and osteogenesis is needed in order to develop new and targeted therapeutic strategies for the treatment of bone diseases/disorders.     

Genetic research in osteoporosis: Where are we? Where should we go next?

Fractures resulting from low bone mass and excessive skeletal fragility (osteoporosis) are common worldwide both in males and females, particularly in later years of life. Both fractures, and the most important predictor of fractures, bone mass, are now known to be strongly heritable. This fact, plus the current growth in genetic science, has led to a surge of genetic research in osteoporosis, mostly in the search for genes and their polymorphisms that are responsible for variation in bone mass. Finding the genetic basis underlying variation in bone mass will lead us to deeper understanding of the biology of bone mass accumulation, maintenance and adaptation to load. This, plus finding the genetic basis for overall variation in fracture risk per se, will facilitate the development of interventions, both pharmaceutical and non-pharmaceutical, to prevent and/or treat osteoporosis successfully. This research has produced a rather large number of gene loci that seem to influence bone mass. The challenge now is to refine the statistical genetics and the phenotypes involved so that we can confidently identify those gene loci that truly influence bone mass, and to find ways to study the genetic basis for the most direct disease outcome of interest, fracture.     

Current perspectives on NMDA-type glutamate signalling in bone

Bone is a complex, evolving tissue, architecturally defined by the activities of osteoclasts and osteoblasts that continually resorb and replace the mineralised matrix. Numerous regulatory mechanisms exist to control bone remodelling and the maintenance of bone mass. The consequences of inappropriate or uncoupled bone resorption and formation are significant and invariably lead to different disease states, the most prevalent being osteoporosis. In recent years, much attention has focused on unravelling the systemic and local signalling interactions that influence the differentiation and function of bone cells with a view to developing our understanding of bone biology and identifying potential new targets for therapeutic intervention. Several lines of evidence indicate that neurotransmitters and neuromodulators have influential roles to play in the regulation of bone remodelling and much of this research has involved analysis of the excitatory amino acid glutamate. This review will summarise current understanding of glutamate signalling in bone cells, addressing specifically the function of N-methyl-D-aspartate (NMDA)-type glutamate receptor signalling mechanisms, and will address the functional significance and future prospects for this area of research.     

Understanding of stem cells in bone biology and translation into clinical applications

Developments of stem cell biology provide new approaches for understanding the mechanisms of a number of diseases, including osteoporosis. In this minireview, we highlight two areas that related to stem cells in bone biology. Recent discovery of the role of osteoclast and their stem cells leads to developing a new approach for treatment of osteoporosis with the initial stimulation of cells in osteoclast lineage and followed by sequentially enhanced bone formation. Stimulation on both sides in bone remodeling is expected to achieve a long term effect on bone formation. For bone regeneration, multiple disciplinary collaborations among bone biologists, stem cell biologists and biomaterial scientists are necessary to successfully develop an integrated stem cell therapy that should include stem cells, suitable scaffolds and bioactive factors/small molecular compounds.     

Pathogenic mutations and polymorphisms in the lipoprotein receptor-related protein 5 reveal a new biological pathway for the control of bone mass

PURPOSE OF REVIEW: This review summarizes recent findings concerning the genomic variations of the lipoprotein receptor-related protein 5 (LPR5) in relation to bone biology. RECENT FINDINGS: Mutations in the LRP5 gene causing high bone mass (HBM) and osteoporosis-pseudoglioma (OPPG) underscored the role of the Wnt-LRP5 canonical signaling on bone formation. Additional LRP5 activating mutations have been identified in a variety of sclerosing bone dysplasias, improving the diagnostic classification of these disorders. Association of polymorphisms in LRP5 with bone mineral density indicate that LRP5 genetic variation contribute to the risk of osteoporosis. Transgenic mice carrying the LRP5 HBM mutation have improved bone biomechanical properties, and the molecular mechanisms by which this mutation exerts its effects have been clarified. A number of KO mice have shown the complex effects of the Wnt-LRP5 pathway on bone mass and skeletal morphology. In vitro studies indicate that osteoblasts produce a variety of Wnts, the LRP5 co-receptor frizzled (Fzd), as well as LRP5 and Wnt inhibitors, i.e. dickkopf (Dkk1) and frizzled-related proteins (Sfrps), respectively, and delineate the role of these molecules in regulating the commitment of mesenchymal stem cells along the osteoblastic lineage. SUMMARY: Identification of pathogenic mutations and allelic variations in LRP5 has improved our understanding of the physiology of bone mass acquisition and the pathophysiology of several bone diseases, including osteoporosis. Understanding how complex interactions between agonistic and inhibitory factors in the Wnt-LRP5 canonical pathway influence osteoblast functions has the potential of providing new anabolic treatments for osteoporosis.     

Mechanisms of glucocorticoid action in bone cells

Glucocorticoids play an important role in the normal regulation of bore remodeling; however continued exposure of bone to glucocorticoid excess results in osteoporosis. In vivo, glucocorticoids stimulate bone resorption and decreasae bone formation, and in vitro studies have shown that while glucocorticoids stimulateosteoblastic differentiation, they have important inhibitory actions on bone formation. Glucocorticoids have manyeffects on osteoblast gene expression, including down-regulation of type 1 collagen and osteocalcin, and up-regulation of interstitial collagenase. The synthesis and activity of osteoblast growth factors can be modulated by glucocorticoids as well. For example, insulin-like growth factor 1 (IGF-1) is an important stimulator of osteoblast function, and expression of IGF-1 is decreased by glucocorticoids. The activity of IGF 1 can be modified by IGF binding proteins (IGFBPs), and theirsynthesis is also regulated by glucocorticoids. Thus, glucocorticoid action on osteoblasts can be direct, by activating or repressing osteoblast gene expression, or indirect by altering the expression or activity of osteoblast growth factors. Further investigation of the mechanisms by which glucocorticoids mnodulate gene expression in bore cells will contribute to our understanding or steroid hormone biology and will provide a basis for the design of effective treatments for glucocorticoid-induced osteoporosis.     

The two faces of serotonin in bone biology

The serotonin molecule has some remarkable properties. It is synthesized by two different genes at two different sites, and, surprisingly, plays antagonistic functions on bone mass accrual at these two sites. When produced peripherally, serotonin acts as a hormone to inhibit bone formation. In contrast, when produced in the brain, serotonin acts as a neurotransmitter to exert a positive and dominant effect on bone mass accrual by enhancing bone formation and limiting bone resorption. The effect of serotonin on bone biology could be harnessed pharmacologically to treat diseases such as osteoporosis.     

Stem cells and regenerative medicine

Stem cells have been defined as clonogenic cells that undergo both self-renewal and differentiation to more committed progenitors and functionally specialized mature cells. Of late years, stem cells have been identified in a variety of tissues of an adult body. Depending on the source, they have the potential to form one or more, or even all cell types of an organism. Stem cell research provided some outstanding contributions to our understanding of developmental biology and offered much hope for cell replacement therapies overcoming a variety of diseases. The establishment of human ES cell lines enabled us to generate all tissues we comprise. Recently, excitement has been evoked by the controversial evidence that adult stem cells have a much higher degree of developmental plasticity than previously imagined. More recently, the existence of multipotent somatic stem cells in bone marrow has been reported. Combined with these discoveries and achievements as well as the developing technologies, scientists are now trying to bring stem cell therapies to the clinic.     

Culture evolves

Culture pervades human lives and has allowed our species to create niches all around the world and its oceans, in ways quite unlike any other primate. Indeed, our cultural nature appears so distinctive that it is often thought to separate humanity from the rest of nature and the Darwinian forces that shape it. A contrary view arises through the recent discoveries of a diverse range of disciplines, here brought together to illustrate the scope of a burgeoning field of cultural evolution and to facilitate cross-disciplinary fertilization. Each approach emphasizes important linkages between culture and evolutionary biology rather than quarantining one from the other. Recent studies reveal that processes important in cultural transmission are more widespread and significant across the animal kingdom than earlier recognized, with important implications for evolutionary theory. Recent archaeological discoveries have pushed back the origins of human culture to much more ancient times than traditionally thought. These developments suggest previously unidentified continuities between animal and human culture. A third new array of discoveries concerns the later diversification of human cultures, where the operations of Darwinian-like processes are identified, in part, through scientific methods borrowed from biology. Finally, surprising discoveries have been made about the imprint of cultural evolution in the predispositions of human minds for cultural transmission.     

Bone diseases associated with human immunodeficiency virus infection: pathogenesis, risk factors and clinical management

Bone disorders such as osteopenia and osteoporosis have been recently reported in patients infected with the human immunodeficiency virus (HIV), but their etiology remains still unknown. The prevalence estimates vary widely among the different studies and can be affected by concomitant factors such as the overlapping of other possible conditions inducing bone loss as lypodystrophy, advanced HIV-disease, advanced age, low body weight or concomitant use of other drugs. All the reports at the moment available in the literature showed a higher than expected prevalence of reduced bone mineral density (BMD) in HIV-infected subjects both na?ve and receiving potent antiretroviral therapy compared to healthy controls. This controversial can suggest a double role played by both antiretroviral drugs and HIV itself due to immune activation and/or cytokines disregulation. An improved understanding of the pathogenesis of bone disorders can result in better preventative and therapeutic measures. However, the clinical relevance and the risk of fractures remains undefined in HIV-population. The clinical management of osteopenia and osteoporosis in HIV-infected subjects is still being evaluated. Addressing potential underlying bone disease risk factors (e.g., smoking and alcohol intake, use of corticosteroids, advanced age, low body weight), evaluating calcium and vitamin D intake, and performing dual x-ray absorptiometry in HIV-infected individuals who have risk factors for bone disease can be important strategies to prevent osteopenia and osteoporosis in this population. The administration of bisphosphonates (e.g., alendronate), with calcium and vitamin D supplementation, may be a reasonable and effective option to treat osteoporosis in these subjects.     

绝经期女性血脂及血压水平与糖尿病骨质疏松的关系

目的：探讨绝经期女性血脂及血压与糖尿病骨质疏松发生的关系。方法：选取2014 年3 月-2015 年5 月在我院接受治疗的 绝经期女性糖尿病患者100 例作为研究对象,根据骨密度不同将患者分为骨质疏松组和非骨质疏松组。检测并比较两组研究对 象的血脂及血压水平,分析其与骨质疏松发生的关系。结果：骨质疏松组患者总胆固醇（TC）、三酰甘油（TG）、高密度脂蛋白胆固 醇（HDL-C）及低密度脂蛋白胆固醇（LDL-C）水平均高于非骨质疏松组,差异具有统计学意义（P<0.05）;与非骨质疏松组比较,骨 质疏松组患者舒张压（DBP）升高,而收缩压（SBP）降低,差异具有统计学意义（P<0.05）;Pearson相关性分析结果显示,年龄、总胆 固醇（TC）及低密度脂蛋白胆固醇（LDL-C）与双股骨骨密度呈正相关关系（P＜0.05）,与腰椎骨密度呈负相关关系（P＜0.05）;Logistic 回归分析结果显示,年龄、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）及收缩压（SBP）是糖尿病骨质疏松发生的危险因素 （P<0.05）。结论：绝经期女性糖尿病患者的年龄、总胆固醇、LDL-C 及收缩压与骨质疏松密切相关,临床应给予重视并采取有效措 施进行预防。     

Current indications for prevention and therapy of steroid-induced osteoporosis in men and women

Steroid-induced osteoporosis is a textbook example of the secondary type of this medical condition. Glucocorticosteroids suppress bone formation by their direct and indirect effect on osteoblasts, osteoclasts and osteocytes, increasing their resorption and, eventually, leading to negative bone balance. A clinical problem arises regarding the fact that approximately 50% of patients on chronic steroid therapy undergo asymptomatic bone fractures. The treatment mode includes minimising the dose of administered steroids, encouraging an improved lifestyle and supplementation with adequate calcium and vitamin D(3) doses. Bisphosphonates are a group of medical agents used both to prevent and treat steroid-induced osteoporosis, although new therapies have also become available in recent years.     

An integrated approach to assess structure-to-function relationships in the skeleton

In general, the disciplines of biomechanics, morphology, densitometry, biochemistry, cell biology and molecular biology have advanced independently of one another. In spite of this fragmentation, there have been incremental increases in our understanding of the organization, mechanical properties, growth, remodeling and repair of the tissues comprising the skeleton. As a practical application, this increased knowledge has greatly improved our capabilities for early diagnosis of bone loss and has proven similarly useful in determining the efficacy of interventions to prevent osteoporosis. This approach, however, has been much less successful in countering several other important musculoskeletal disorders, including arthritis. In the immediate future, a major emphasis will be placed on tissue regeneration (engineering) to restore lost mechanical function to a compromised skeleton. To accomplish this goal, it will be necessary to employ much more sophisticated approaches toward evaluating the structure-to-function relationships, ones which will include integration of the respective contributions of gene expression, cell number and activity, matrix composition and architecture to achieve adequate tissue function.     

Current indications for prevention and therapy of steroid-iduced osteoporosis in men and women

Steroid-induced osteoporosis is a textbook example of the secondary type of this medical condition. Glucocorticosteroids suppress bone formation by their direct and indirect effect on osteoblasts, osteoclasts and osteocytes, increasing their resorption and, eventually, leading to negative bone balance. A clinical problem arises regarding the fact that approximately 50% of patients on chronic steroid therapy undergo asymptomatic bone fractures. The treatment mode includes minimising the dose of administered steroids, encouraging an improved lifestyle and supplementation with adequate calcium and vitamin D3 doses. Bisphosphonates are a group of medical agents used both to prevent and treat steroid-induced osteoporosis, although new therapies have also become available in recent years.     

Prospect of mesenchymal stem cells in therapy of osteoporosis: A review

Osteoporosis is a systemic skeletal disease associated with reduced bone strong point that results in raised fracture risk, with decreased bone strength, leading to reduced bone mineral density and poor bone quality. It is the most common in older females but some men are also at high risk. Although considered as a predictable result of aging, it is can be avoidable and treatable. The existing treatment of osteoporosis mainly contains antiresorptive and anabolic agents. In spite of these improvements, concerns around unusual side-effects of antiresorptive drugs, and the lack of perfect confirmation in maintenance of their long-standing effectiveness is bring about many patients not receiving these drugs. Over the years, the stem cell-based therapy has attained substantial clinical consideration because of its potential to treat numerous diseases. The stem cell therapy has been recommended as a probable therapeutic approach for patients with osteoporosis. Even though the concept of stem cell-based therapy for osteoporosis has caught substantial attention, no clinical trial has been published on humans. The cell studies based on osteoporosis are primarily focused on osteoclastic activity and bone resorption procedures. Earlier, it was on osteoblastogenesis and in recent times, on the differentiation probable of mesenchymal stem cells. In this review, we have summarized the therapeutic role of stem cell-based strategy in osteoporosis.     

The incredible elastic brain: how neural stem cells expand our minds

Brain development was thought to be largely hardwired and accomplished by birth, and the brain was thought to have essentially no regenerative capacity. The remarkable discovery of adult neurogenesis and neural stem cells (NSCs) existing in the mature CNS changed that, allowing us to think optimistically about CNS repair. These discoveries helped to generate a robust field of neural progenitor cell biology, with relevance to CNS development, pathogenesis, the search for novel neurological therapies, as well as our understanding of how the brain works.     

Bugs, drugs and chemical genomics

The serendipitous discovery of penicillin inspired intensive research into how small molecules affect basic cellular processes and their potential to treat disease. Biochemical and genetic approaches have been fundamental for clarifying small-molecule modes of action. Genomic technologies have permitted the use of chemical-genetic strategies that comprehensively study compound-target relationships in the context of a living cell, providing a systems biology view of both the cellular targets and the interdependent networks that respond to chemical stress. These studies highlight the fact that in vitro determinations of mechanism rarely translate into a complete understanding of drug behavior in the cell. Here, we review key discoveries that gave rise to the field of chemical genetics, with particular attention to chemical-genetic strategies developed for bakers' yeast, their extension to clinically relevant microbial pathogens, and the potential of these approaches to affect antimicrobial drug discovery.