Skeletal and non-skeletal roles for osteocalcin

骨钙素是骨骼中表达最高的蛋白质之一。基于使用 Ocnm1系骨钙素基因敲除(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、男性生育能力、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在小鼠和人类中的许多下游研究，这产生了 结果不一致，甚至相互矛盾。两个独立产生并检测的新菌株 骨钙素KO小鼠(BGLAP/2DKO和OCN-)没有糖代谢、脂肪储存、雄性生育、 或肌肉质量；在2个新的KO菌株中没有检测到神经学表型。不一致的发现 在原始的(Ocnm1)和新的(Bgap/2dko和OCN-)骨钙素KO菌株之间创造了一个挑战和 机会。挑战是确定最初报道的哪些激素表型是健壮的(即，真的 阳性)，以及这些表型是否在新的KO菌株中被遗漏(即假阴性)。 如果之前公布的数据是正确的，机会就会出现，因为这将意味着 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) 哪些动物被饲养(或研究)是否以及如何影响骨钙素缺乏？ 新陈代谢、生育能力、衰老和认知。我们将确定在原始Ocnm1 KO株和 在BGLAP/2dko KO品系中，是否有任何一致的表型(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将在其最安全的隔膜中扩展每个菌株，以最大限度地减少环境污染 混血儿。贾克斯将对每个菌株的动物进行基因分型，并将它们送到研究新陈代谢的专家实验室， 生殖、肌肉、神经和骨骼表型；这些专家实验室将盲目地进行表型分析 对动物株(Ocnm1或Bgap/2dko)和基因型(WT或KO)。表型数据将发送给研究人员 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，全部 --美国骨矿研究学会前会长。源自这部作品的手稿 将发表在BioRxiv上，并提交给开放获取、同行审查的期刊。表现得很好， 专家实验室使用在公共环境中饲养的可公开获得的小鼠进行盲法研究， 并由骨骼生物学领域受人尊敬的领导人进行审查，对于解决有关 骨钙素的内源性作用和识别因素(如KO等位基因、遗传背景、环境) 这可能会改变骨钙素缺乏在小鼠品系之间和人类种群之间的影响。

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.