Skeletal and non-skeletal roles for osteocalcin

骨钙素的骨骼和非骨骼作用

• 批准号: 10595042
• 负责人: Matthew L Warman
• 金额: $ 40.57万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595042
• 关键词: Affect; African American; Aging; Alleles; American; Animal Behavior; Animals; Apatites; Behavioral; Biological; Biological Markers; Biological Process; Biology; Blinded; Blood Glucose; Body mass index; Bone Density; Boston; Brain; Child; Cognition; Cultured Cells; Data; Deposition; Development; Diabetes Mellitus; Diet; Dietary intake; Disease; Drug Targeting; Ear; Endocrine; Energy Metabolism; Ensure; Environment; Environmental Exposure; Evolution; Failure; Fatty acid glycerol esters; Fertility; Funding Agency; Genetic; Genetic Variation; Genotype; Glucose; Glucose Clamp; Glycosylated hemoglobin A; Grant; Health; Hormonal; Hormones; Hospitals; Human; Human Resources; Hydroxyapatites; Hyperglycemia; Impaired cognition; Impairment; Individual; Induced Mutation; Insulin; Insulin Resistance; Investments; Journals; Knock-out; Knockout Mice; Laboratories; Learning; Letters; Literature; Manuscripts; Measures; Medicine; Metabolic; Metabolism; Minerals; Morphology; Mouse Strains; Mus; Muscle; Nature; Neurologic; Osteocalcin; Patients; Pediatric Hospitals; Peer Review; Pharmacologic Substance; Phenotype; Physiology; Population; Post-Translational Protein Processing; Production; Property; Proteins; Publishing; Quarantine; Rattus; Recombinants; Reporting; Reproducibility; Reproduction; Reproductive Biology; Research; Resources; Risk; Role; Science; Societies; Sperm Count Procedure; Testis; The Jackson Laboratory; Therapeutic; Therapeutic Agents; Translating; United States National Institutes of Health; Universities; Validation; Vitamin K; Work; age-related muscle loss; bisphosphonate; bone; bone mass; bone strength; brain malformation; cohort; college; conflict resolution; experimental study; fascinate; fighting; follower of religion Jewish; genome wide association study; glucose metabolism; glucose tolerance; inhibitor; insulin tolerance; loss of function; loss of function mutation; male fertility; medical schools; metabolic abnormality assessment; metabolic phenotype; microbiome; muscle form; nanoindentation; novel; phenotypic data; programs; protein function; reproductive; reproductive hormone; response; skeletal

Osteocalcin is among the most highly expressed proteins in bone. Based on studies performed using the Ocnm1 strain of osteocalcin knockout (KO) mice, osteocalcin was suggested to be a bone-derived hormone that regulates glucose metabolism, fat storage, male fertility, muscle mass, brain development, and cognition. These novel and exciting roles for osteocalcin led to many downstream studies in mice, and in humans, which yielded inconsistent and even contradictory results. Two independently generated and examined new strains of osteocalcin KO mice (Bglap/2dko and Ocn-) did not have abnormal glucose metabolism, fat storage, male fertility, or muscle mass; neurologic phenotypes were not examined in the 2 new KO strains. The inconsistent findings between the original (Ocnm1) and new (Bglap/2dko and Ocn-) osteocalcin KO strains creates a challenge and an opportunity. The challenge is to determine which originally reported hormonal phenotypes are robust (i.e., true positives), and whether these phenotypes may have been missed (i.e., false negatives) in the new KO strains. Opportunity arises if the previously published data are correct, since this would mean that differences between the specific KO allele, the genetic background (e.g., 129 vs C57), or the environment (e.g., diet, microbiome) in which animals were raised (or studied) are responsible for whether and how osteocalcin deficiency affects metabolism, fertility, ageing, and cognition. We will determine which findings in the original Ocnm1 KO strain and in the Bglap/2dko KO strain are robust, and whether there are any consistent phenotypes (e.g., behavioral, bone apatite crystal orientation) across strains. These are possible now that both strains are available from The Jackson Laboratory (JAX). JAX will expand each strain in its maxi-safe vivarium to minimize environmental confounders. JAX will genotype and ship animals from each strain to laboratories expert in studying metabolic, reproductive, muscle, neurologic, and skeletal phenotypes; these expert labs will perform phenotyping blinded to animal strain (Ocnm1 or Bglap/2dko) and genotype (WT or KO). Phenotype data will be sent to the study statistician, PI, and Data Review Panel for review. The Data Review Panel has 4 expert skeletal biologists, all past-Presidents of the American Society for Bone and Mineral Research. Manuscripts deriving from this work will be posted on BioRxiv and submitted to open-access, peer-reviewed, journals. Performing well-powered, blinded studies using publicly available mice raised in a common environment, studied by expert laboratories, and reviewed by respected leaders in the field of skeletal biology is essential for resolving conflicts regarding the endogenous role of osteocalcin and for identifying factors (e.g., KO allele, genetic background, environment) that may modify the effect of osteocalcin deficiency between mouse strains and between human populations.

骨钙素是骨中表达最高的蛋白质之一。基于使用 Ocnm 1品系的骨钙素敲除（KO）小鼠，骨钙素被认为是一种骨源性激素， 调节葡萄糖代谢、脂肪储存、男性生育力、肌肉质量、大脑发育和认知。这些 骨钙素的新的和令人兴奋的作用导致了许多在小鼠和人类中的下游研究，这些研究产生了 不一致甚至矛盾的结果。两个独立产生和检测的新菌株 骨钙素KO小鼠（Bglap/2dko和Ocn-）没有异常的葡萄糖代谢、脂肪储存、雄性生育力 或肌肉质量;在2个新KO菌株中未检查神经学表型。该不一致的结果 原始（Ocnm 1）和新（Bglap/2dko和Ocn-）骨钙素KO菌株之间的差异产生了挑战和 机会挑战在于确定哪些最初报告的激素表型是稳健的（即，真 阳性），以及这些表型是否可能被遗漏（即，假阴性）。 如果先前发布的数据是正确的，则会出现机会，因为这意味着 特定的KO等位基因，遗传背景（例如，129对C57），或环境（例如，饮食，微生物组） 饲养（或研究）的动物是否和如何影响骨钙素缺乏症 新陈代谢、生育、衰老和认知。我们将确定在原始Ocnm 1 KO菌株和 在Bglap/2dko KO株中的稳定性，以及是否存在任何一致的表型（例如，行为，骨骼 磷灰石晶体取向）。现在这两种菌株都可以从 杰克逊实验室（JAX）。JAX将在其最安全的动物园中扩大每种菌株，以最大限度地减少环境污染。 混杂因素。JAX将对每种品系动物进行基因分型， 生殖、肌肉、神经和骨骼表型;这些专家实验室将在设盲的情况下进行表型分析 对动物品系（Ocnm 1或Bglap/2dko）和基因型（WT或KO）进行鉴定。表型数据将发送至研究 统计学家、PI和数据审查小组进行审查。数据审查小组有4名骨骼生物学家专家，均 美国骨矿物质研究学会前任主席。源自该作品的手稿 将在BioRxiv上发布，并提交给开放存取、同行评审的期刊。性能强劲、 使用在普通环境中饲养的公众可获得的小鼠的盲法研究，由专家实验室研究， 并由骨骼生物学领域受人尊敬的领导人进行审查，对于解决 骨钙素的内源性作用和鉴定骨钙素的因子（例如，KO等位基因、遗传背景、环境） 这可能会改变小鼠品系之间和人类群体之间骨钙素缺乏的影响。