The need for mouse models in osteoporosis genetics research.
Ontology highlight
ABSTRACT:
SUBMITTER: Ackert-Bicknell CL
PROVIDER: S-EPMC3727715 | biostudies-other | 2012
REPOSITORIES: biostudies-other
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Project description:Limited knowledge of the genetic causes of male infertility has resulted in few treatment and targeted therapeutic options. Although the ideal approach to identify infertility causing mutations is to conduct studies in the human population, this approach has progressed slowly due to the limitations described herein. Given the complexity of male fertility, the entire process cannot be modeled in vitro. As such, animal models, in particular mouse models, provide a valuable alternative for gene identification and experimentation. Since the introduction of molecular biology and recent advances in animal model production, there has been a substantial acceleration in the identification and characterization of genes associated with many diseases, including infertility. Three major types of mouse models are commonly used in biomedical research, including knockout/knockin/gene-trapped, transgenic and chemical-induced point mutant mice. Using these mouse models, over 400 genes essential for male fertility have been revealed. It has, however, been estimated that thousands of genes are involved in the regulation of the complex process of male fertility, as many such genes remain to be characterized. The current review is by no means a comprehensive list of these mouse models, rather it contains examples of how mouse models have advanced our knowledge of post-natal germ cell development and male fertility regulation.
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Project description:BackgroundOsteoporosis (OP), a systemic skeletal disease common in aged population, is an important public health problem worldwide. Animal models are important tools for understanding OP. In ovariectomy (OVX) or orchiectomy (ORX) OP models, lumbar vertebrae are often used for evaluating of the OP progression. However, unlike the bipeds, the lumbar vertebrae are not weight loading bones in quadruped animal, but the head-bearing cervical vertebrae take much higher stress. So, we compared the murine cervical vertebrae with lumbar vertebrae for OP assessment.MethodsOVX and ORX mouse models were established on C57BL/6J mice. Serum estradiol, testosterone and bone related biomarkers were verified. Bone quantity and quality were determined using micro computed tomography (micro-CT) analysis. Hard tissue sections were prepared, stained for histomorphological analyzing, and micro-indentation measured for bone mechanical property evaluation.ResultsIn OVX and ORX mice, serum estradiol or testosterone levels reduced, bone resorption level and related biomarkers elevated, indicated the successful generation of the OP models. In the early stage, the trabecular bone mineral density (BMD) of cervical vertebrae was already reduced 16.1% (OVX) and 21.7% (ORX) one-month post-gonadectomy, respectively; while this decline in the fifth lumbar vertebra were only 5% and 7.4%, respectively. Six months post-gonadectomy, the reduction of BMD in cervical vertebrae and the fifth lumbar vertebra were 31.2% & 36.1% and 28.5% & 30.7% respectively. In biomechanical aspects, cervical spines showed worse Vickers hardness (HV) and elastic modulus than lumbar spine in six-month OVX and ORX mice.ConclusionsWe provide a new OP early-stage evaluation mouse model based on the cervical spine. Through the radiographic, biological and biomechanical assessments, the mouse cervical spine is more suitable for bone remodeling evaluation in OP models than the conventional lumbar vertebrae, especially for early-stage OP study.
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Project description:Increased rates of osteoporotic fractures represent a worldwide phenomenon, which result from a progressing aging in the population around the world and creating socioeconomic problems. This review will focus mostly on human genetic studies identifying genomic regions, genes and mutations associated with osteoporosis (bone mineral density (BMD) and bone loss) and related fractures, which were published during 2011. Although multiple genome-wide association studies (GWAS) were performed to date, the genetic cause of osteoporosis and fractures has not yet been found, and only a small fraction of high heritability of bone mass was successfully explained. GWAS is a successful tool to initially define and prioritize specific chromosomal regions showing associations with the desired traits or diseases. Following the initial discovery and replication, targeted sequencing is needed in order to detect those rare variants which GWAS does not reveal by design. Recent GWAS findings for BMD included WNT16 and MEF2C. The role of bone morphogenetic proteins in fracture healing has been explored by several groups, and new single-nucleotide polymorphisms present in genes such as NOGGIN and SMAD6 were found to be associated with a greater risk of fracture non-union. Finding new candidate genes, and mutations associated with BMD and fractures, also provided new biological connections. Thus, candidates for molecular link between bone metabolism and lactation (for example, RAP1A gene), as well as possible pleiotropic effects for bone and muscle (ACTN3 gene) were suggested. The focus of contemporary studies seems to move toward whole-genome sequencing, epigenetic and functional genomics strategies to find causal variants for osteoporosis.
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Project description:We illustrate the growing power of the BXD family of mice (recombinant inbred strains from a cross of C57BL/6J and DBA/2J mice) and companion bioinformatic tools to study complex genome-phenome relations related to glaucoma. Over the past 16 years, our group has integrated powerful murine resources and web-accessible tools to identify networks modulating visual system traits-from photoreceptors to the visual cortex. Recent studies focused on retinal ganglion cells and glaucoma risk factors, including intraocular pressure (IOP), central corneal thickness (CCT), and susceptibility of cellular stress. The BXD family was exploited to define key gene variants and then establish linkage to glaucoma in human cohorts. The power of this experimental approach to precision medicine is highlighted by recent studies that defined cadherin 11 (Cdh11) and a calcium channel (Cacna2d1) as genes modulating IOP, Pou6f2 as a genetic link between CCT and retinal ganglion cell (RGC) death, and Aldh7a1 as a gene that modulates the susceptibility of RGCs to death after elevated IOP. The role of three of these gene variants in glaucoma is discussed, along with the pathways activated in the disease process.
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Project description:The aim of this protocol is to provide a detailed description of male and female rodent models of osteoporosis. In addition to indications on the methods of performing the surgical procedures, the choice of reliable and safe anaesthetics is also described. Post-operative care, including analgesia administration for pain management, is also discussed. Ovariectomy in rodents is a procedure where ovaries are surgically excised. Hormonal changes resulting from ovary removal lead to an oestrogen-deprived state, which enhances bone remodelling, causes bone loss and increases bone fracture risk. Therefore, ovariectomy has been considered as the most common preclinical model for understanding the pathophysiology of menopause-associated events and for developing new treatment strategies for tackling post-menopausal osteoporosis. This protocol also provides a detailed description of orchidectomy, a model for androgen-deficient osteoporosis in rodents. Endocrine changes following testes removal lead to hypogonadism, which results in accelerated bone loss, increasing osteoporosis risk. Orchidectomised rodent models have been proposed to mimic male osteoporosis and therefore remain a valuable tool for understanding androgen deficiency in aged men. Although it would have been particularly difficult to assemble an internationally acceptable description of surgical procedures, here we have attempted to provide a comprehensive guide for best practice in performing ovariectomy and orchidectomy in laboratory rodents. Research scientists are reminded that they should follow their own institution's interpretation of such guidelines. Ultimately, however, all animal procedures must be overseen by the local Animal Welfare and Ethical Review Body and conducted under licences approved by a regulatory ethics committee.
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