Bone metabolism: a note on the significance of mouse models

This minireview briefly surveys the complexity of regulations governing the bone metabolism. The impact of clinical studies devoted to osteoporosis is briefly summarized and the emphasis is put on the significance of experimental mouse models based on an extensive use of genetically modified animals. Despite possible arising drawbacks, the studies in mice are of prime importance for expanding our knowledge on bone metabolism. With respect to human physiology and medicine, one should be always aware of possible limitations as the experimental results may not be, or may be only to some extent, transposed to humans. If applicable to humans, results obtained in mice provide new clues for assessing unforeseen treatment strategies for patients. A recent publication representing in our opinion the important breakthrough in the field of bone metabolism in mice is commented in detail. It provides an evidence that skeleton is endocrine organ that affects energy metabolism and osteocalcin, a protein specifically synthesized and secreted by osteoblasts, is a hormone involved. If confirmed by other groups and applicable to humans, this study provides the awaited connection of long duration between bone disorders on one hand and obesity and diabetes on the other.     

Bone As An Endocrine Organ

ObjectiveTo review the recent evidence that has emerged supporting the role of bone as an endocrine organ.MethodsThis review will detail how bone has emerged as a bona fide endocrine “gland,” and with that, the potential therapeutic implications that could be realized for this hormone-secreting tissue by detailing the evidence in the literature supporting this view.ResultsThe recent advances point to the skeleton as an endocrine organ that modulates glucose tolerance and testosterone production by secretion of the bone-specific protein osteocalcin.ConclusionsBone has classically been viewed as an inert structure that is necessary for mobility, calcium homeostasis, and maintenance of the hematopoietic niche. Recent advances in bone biology using complex genetic manipulations in mice have highlighted the importance of bone not only as a structural scaffold to support the human body, but also as a regulator of a number of metabolic processes that are independent of mineral metabolism. (Endocr Pract. 2012;18:758-762)     

Osteocalcina: nexo de unión entre homeostasis ósea y metabolismo energético

Research in animal models has demonstrated the role of osteocalcin, a bone formation marker, in regulation of energy metabolism. Those studies have led to a new concept of the bone acting as an endocrine organ by secreting osteocalcin, which acts by increasing insulin secretion, lowering plasma glucose, and increasing insulin sensitivity and energy expenditure. Results in humans have been conflicting. On the other hand, antiresorptive drugs used against osteoporosis decrease osteocalcin levels, while anabolic drugs increase osteocalcin levels. However, the effects of these therapies on energy metabolism have not been investigated.     

Co-dependence of bone and energy metabolisms

The growing number of genetically modified mouse models available but also of the possibility to delete one or several genes at will in a defined time frame or in a specific cell type or tissue(s) has open new possibilities for the study of whole animal physiology. This in vivo approach has been especially successful in uncovering a regulatory loop linking the control of energy metabolism and the regulation of bone remodeling. This review is intended to summarize the key events that led to the identification and the characterization of the different steps and molecules constituting this regulatory network.     

Transgenic and knock out mice in skeletal research. Towards a molecular understanding of the mammalian skeleton

Our understanding of the biology of the skeleton, like that of virtually every other subject in biology, has been transformed by recent advances in human and mouse genetics. Among mammals, mice are the most promising animals for this experimental work. Because extensive genetic information exists, many mouse mutations are known, and cells from early mouse developmental stages are accessible, scientists have developed transgenic mice - mice in which a gene is introduced or ablated in the germ line. Thus far, we have analyzed more than 100 different transgenic and knock out models with various skeletal phenotypes, covering the major aspects of both skeletal development and skeletal maintenance. Based on these results we here present a first perspective on transgenic and gene knock out animals in skeletal research, including insights in signaling pathways controlling endochondral bone formation, in the regulation of osteoblast function, osteoclastic bone resorption and in bone tumorigenesis, as well as the central control of bone formation. The use of transgenic mice to dissect and analyze regulatory mechanisms in bone cell physiology and the pathogenesis of human bone diseases is an extremely powerful experimental tool. The data presented here demonstrate that the successful convergence of novel genetic approaches with the established and fundamental knowledge of bone biology has made a beginning.     

骨源活性物质的中枢调控功能

骨是机体的主要支持结构,也是参与机体运动和钙磷代谢的主要器官.骨也是一种潜在的新型内分泌器官,其通过骨细胞和骨髓分泌的多种生物活性物质,参与心血管、消化、内分泌等多个系统的生理和病理生理过程.骨源活性物质还可直接作用于中枢神经系统,参与脑功能和个体行为的调节,骨-脑轴的双向调控也逐渐引起了神经科学研究领域的关注.本文综...     

Mouse phenogenomics: the fast track to "systems metabolism"

With the completion of the many genomes, genetics is positioned to meet physiology. In this review, we summarize the coming of "systems metabolism" in mammals through the use of the mouse, as a model system to study metabolism. Building on mouse genetics with increasingly sophisticated clinical and molecular phenotyping strategies has enabled scientists to now tackle complex biomedical questions, such as those related to the pathogenesis of the common metabolic disorders. The ultimate goal of such strategies will be to mimic human metabolism with the click of a mouse.     

Genetic control of skeletal development

The skeleton is a single organ composed of >200 different elements spread throughout the body. These skeletal elements comprise two tissues: cartilage and bone. Both tissues contain specific cell type(s): chondrocytes in cartilage and osteoblasts and osteoclasts in bone. We are beginning to understand the genetic control of the differentiation and function of these cells through recent developments in mouse and human genetics, and also through the use of molecular biological and biochemical techniques. The most recent advances in terms of cell differentiation in the skeleton are presented in this review.     

Systemic regulation of adipose metabolism

White adipose tissue serves as a critical energy storage depot and endocrine organ. Adipocytes are subject to numerous levels of regulation, including neuronal, endocrine and metabolic. While insulin is the classical endocrine regulator of lipid metabolism in adipose tissue, other important endocrine hormones also control adipose tissue physiology. In this review, we will focus on the contribution of the pituitary in the modulation of adipocyte function, through the direct release of growth hormone as well as via the regulation of the thyroid gland and release of thyroid hormone. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.     

Hormonal and nutritional regulation of insect fat body development and function

The insect fat body is an organ analogue to vertebrate adipose tissue and liver and functions as a major organ for nutrient storage and energy metabolism. Similar to other larval organs, fat body undergoes a developmental “remodeling” process during the period of insect metamorphosis, with the massive destruction of obsolete larval tissues by programmed cell death and the simultaneous growth and differentiation of adult tissues from small clusters of progenitor cells. Genetic ablation of Drosophila fat body cells during larval‐pupal transition results in lethality at the late pupal stage and changes sizes of other larval organs indicating that fat body is the center for pupal development and adult formation. Fat body development and function are largely regulated by several hormonal (i.e. insulin and ecdysteroids) and nutritional signals, including oncogenes and tumor suppressors in these pathways. Combining silkworm physiology with fruitfly genetics might provide a valuable system to understand the mystery of hormonal regulation of insect fat body development and function. © 2009 Wiley Periodicals, Inc.     

Genetic regulation of bone mineral density in mice

Peak bone mass is a major determinant of risk of osteoporotic fracture. Family and twin studies have found a strong genetic component to the determination of bone mineral density (BMD). However, BMD is a complex trait whose expression is confounded by environmental influences and polygenic inheritance. The number, locations and effects of the individual genes contributing to natural variation in this trait are all unknown. The extreme difficulty of dissecting out environmental factors from genetic ones in humans has motivated the investigation of animal models. Genetically distinct animal strains raised under strict environmental control are critical tools for defining genetic regulation. The availability of inbred strains, combined with its relative fecundity, has established the mouse as the best model system for the study of mammalian genetics and physiology. Importantly, genes identified in murine analyses can usually be readily mapped to particular human chromosomal regions because of the high degree of synteny that exists between the mouse and human genomes. We employed quantitative trait locus (QTL) analysis to examine peak BMD in 24 recombinant inbred (RI) mouse strains, derived from a cross between C57BL/6 (B6) and DBA/2 (D2) progenitors (BXD RI). The distribution of BMD values among these strains clearly indicated the presence of strong genetic influences, with an estimated narrow sense heritability of 35%. The differences in peak whole body BMD in the BXD strains were integrated with a large database of genetic markers previously defined in the RI BXD strains to generate chromosome map sites for QTL locations. This QTL analysis provisionally identified a number of chromosomal sites linked to BMD. In the second phase of our BMD QTL mapping efforts, we used three independent mouse populations (all derived from B6 and D2 progenitor strains) to confirm and narrow the genetic locations of 4 QTLs (on chromosomes 1, 2, 4, and 11) that strongly influence the acquisition of peak BMD in mice. Using a novel, fine-mapping approach (recombinant inbred segregation testing), we have succeeded in narrowing two of the BMD-related chromosomal regions and in the process eliminated a number of candidate genes. The homologous regions in the human genome for each of these murine QTLs have been identified in recent human genetic studies. In light of this, we believe that findings in mice should aid in the identification of specific candidate genes for study in humans.     

Quantitative genetics and fitness effects of basal metabolism

The physiological requirements of reproduction are predicted to generate a link between energy, physiology and life history traits. Simultaneously, low maintenance costs, measured by energy consumption, are expected to be advantageous. Here we investigated fitness relatedness of traits by estimating genetic correlations between, and inbreeding depression for, body mass, basal metabolic rate (BMR) and other life history characters in a wild rodent, Myodes glareolus. The narrow-sense heritability of absolute and mass corrected BMRs were high for females (h² = 0.48 and 0.42) but low and non-significant for males (0.32 and 0.09). A significant positive genetic correlation between BMR and litter size suggests that traits connected to female fecundity might favour higher metabolism (i.e. support increased intake hypothesis). However, the estimates of inbreeding depression indicate that, while higher values of body mass and female litter size could be positively associated with overall fitness, the association between BMR and overall fitness in bank voles would be negative (i.e. support compensation hypothesis). This result suggests that the advantages of larger litters and larger body mass might be evolutionary constrained by high costs of maintenance of those traits, as reflected by the level of basal metabolism.     

Vitamin D--soltriol the heliogenic steroid hormone: somatotrophic activator and modulator. Discoveries from histochemical studies lead to new concepts

Evidence from autoradiographic studies with 3H 1,25(OH)2 vitamin D3 (soltriol) about its many sites of nuclear binding and multiple actions suggests that the traditional view of "vitamin D and calcium" is too limited and requires modification. A new concept has been developed which proposes that the skin-derived hormone of sunshine, soltriol, is a somatotrophic activator and modulator that affects all vital systems. Regulation of calcium homeostasis is only one of its many actions. Target tissues for soltriol include not only bone, intestine and kidney, but also brain, spinal cord, pituitary, thyroid, endocrine pancreas, adrenal medulla, enteroendocrine cells, thymus, and male and female reproductive organs. Accordingly, actions of soltriol involve effects on autonomic and endocrine regulation with changes in tissue and blood hormone levels, innervation of skeletal muscle, immune and stress response, digestion, blood formation, fertility, pregnancy and lactation, general energy metabolism, mental processes and mood, and others. The skin-mediated transduction of short-wave sunlight induces a purposeful modulation of growth, reproduction and other biological activities in tune with the conditions of the sun cycle and season. Synthesis and actions of vitamin D3-soltriol are dependent not only on the amount of sunlight, but also on the availability of precursor in the skin and access of sunlight, the rate of hydroxylation in liver and kidney, and the modulation of these events by the endocrine status, in particular growth and reproduction. A concept of a five-level control of soltriol synthesis is proposed, in which the hydroxylation steps provide for a sensitive tuning. Relationships between the heliogenic skin-derived hormonal system and the helioprivic pineal-derived hormonal system are recognized and a comprehensive concept of the "endocrinology of sunlight and darkness" is pointed out.     

What do we know about serotonin?

The present review focuses on what is known of basic serotonin physiology in the human body. Here, we describe serotonin biochemistry and metabolism and summarize the results of studies that have contributed significantly to our understanding of serotonin physiology. We report the well-established role of serotonin in cardiovascular, gastrointestinal, and circulatory physiology. Emphasis is placed on the role of serotonin in peripheral physiological systems rather than in the central nervous system. A brief overview is provided on the emerging role of serotonin in novel areas such as bone pathways and glucose uptake. We also report a select few animal studies and animal models that have provided worthwhile contributions to the understanding of serotonin in human physiology. In addition, we summarize the results of large-scale genetic studies on serotonin and serotonin transporter genes, performed in relation to behavioral and mood disorders.     

The European Renal Genome Project

Rapid progress in genome research creates a wealth of information on the functional annotation of mammalian genome sequences. However, as we accumulate large amounts of scientific information we are facing problems of how to integrate and relate the data produced by various genomic approaches. Here, we propose a novel concept of an organ atlas where diverse data from expression maps to histological findings to mutant phenotypes can be queried, compared and visualized in the context of a three dimensional reconstruction of the organ. We will seek proof of concept for the organ atlas by elucidating genetic pathways involved in development and pathophysiology of the kidney. Such a kidney atlas may provide a paradigm for a new systems-biology approach in functional genome research aimed at understanding the genetic basis of organ development, physiology and disease.     

A neuro (endo)crine regulation of bone remodeling

Bone remodeling is the normal physiologic process that is used by vertebrates to maintain a constant bone mass during the period bracketed by the end of puberty and the onset of gonadal failure in later life. Besides the well-characterized and critical process of local regulation of bone remodeling, achieved by autocrine and paracrine mechanisms, recent genetic studies have shown that there is a central control of bone formation, mediated by a neuroendocrine mechanism. This central regulation involves leptin, an adipocyte-secreted hormone that controls body weight, reproduction and bone remodeling, and which binds to and exerts its effect through the cells of the hypothalamic nuclei in the brain. This genetic result in mice is in line with clinical observations in humans and generates a whole new direction of research in bone physiology. BioEssays 22:970-975, 2000.     

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.     

Molecular Genetics and Developmental Physiology: Implications for Designing Better Forest Crops

Current tree biology related to tree genetics and breeding has two important developments that have not well been integrated in the literature. The first is the physiological and biochemical dissection of plant yield, whereas the second is the genetic mapping based on molecular markers, such as RFLPs, RAPDs, AFLPs, and microsatellites. Genetic mapping has revolutionized traditional quantitative genetic analysis by which the genetic variation of a character is described in terms of its mean and (co)variance without the knowledge of the underlying genes. By integrating physiological and developmental studies of yield traits, genetic mapping can provide a unique means for detecting key QTL that play important roles in affecting tree growth and metabolism. The incorporation of these QTL into commercial populations through gene transformation or marker-assisted selection will move current breeding programs strictly based on an empirism to an approach that is mechanistically oriented. In this review, we discuss how plant physiology and development are merged with genetic mapping to formulate the strategy of molecular breeding in which superior forest crops are selected at the gene level. It is anticipated that this novel breeding strategy can potentially provide major breakthroughs for tree breeding.     

脂肪细胞因子对代谢的调节

脂肪组织可将多余能量以甘油三酯(triglycerides,TG)形式储存,在饥饿状态下可分解TG产生游离脂肪酸(free fatty acids,FFAs)为机体供能。此外,脂肪组织还具有体温调节和器官保护功能,并且越来越多的证据表明,脂肪组织也是一种重要的内分泌组织。脂肪组织分泌的蛋白质物质被称为脂肪细胞因子(adipokine),可通过自分泌、旁分泌和内分泌方式发挥多种生物学功能,例如调节能量摄入和能量消耗,调节糖脂代谢,抗炎和促炎反应。对整体而言,脂肪细胞因子可调节大脑、肝、肌肉、血管系统、心、胰腺和免疫系统等不同靶器官的生物反应。其中,脂肪细胞因子在糖脂代谢中发挥特定的作用,包括:葡萄糖代谢[瘦素(leptin)、脂联素(adiponectin)、抵抗素(resistin)];胰岛素敏感性 [瘦素、脂联素、锌-α2-糖蛋白(zinc-α2-glycoprotein,ZAG)];脂肪形成[骨形成蛋白4(bone morphogenetic protein 4,BMP4)]等生物反应过程。但目前对脂肪组织功能障碍与代谢之间机制的理解尚不完善。脂肪组织功能发生紊乱时,脂肪细胞因子的分泌会发生改变,并可能导致一系列与肥胖相关的代谢性疾病的发生。临床前和临床研究表明,激活或抑制特定脂肪细胞因子的信号转导可能是一种适合干预代谢疾病的方法。本文就部分脂肪细胞因子对代谢的调控作用做出综述,以增强对脂肪细胞因子功能的理解。