Skeletal and non-skeletal roles for osteocalcin

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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.