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Principal Investigator: Matthew L Warman
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $377,718
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
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.
Terms: <0-11 years old><Abnormal Assessment of Metabolism><Affect><African American><Afro American><Afroamerican><Aging><Alleles><Allelomorphs><American><Animal Behavior><Animals><Apatites><BMI><BMI percentile><BMI z-score><Behavioral><Biological><Biological Function><Biological Markers><Biological Process><Biology><Bisphosphonates><Blinded><Blood Glucose><Blood Sugar><Body mass index><Bone 4-Carboxyglutamic Protein><Bone Density><Bone Gla Protein><Bone Mineral Density><Bone gamma-Carboxyglutamic Acid Protein><Boston><Brain><Brain Nervous System><Child><Child Youth><Children (0-21)><Children's Hospital><Cognition><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Common Rat Strains><Cultured Cells><D-Glucose><Data><Deposit><Deposition><Development><Dextrose><Diabetes Mellitus><Diet><Dietary intake><Disease><Disorder><Disturbance in cognition><Drug Targeting><Ear><Encephalon><Endocrine><Endocrine Gland Secretion><Energy Expenditure><Energy Metabolism><Ensure><Environment><Environmental Exposure><Euglycemic Clamping><Evolution><Failure><Fats><Fatty acid glycerol esters><Fecundability><Fecundity><Fertility><Funding Agency><Funding Source><GWA study><GWAS><Genetic><Genetic Diversity><Genetic Variation><Genotype><Glucose><Glucose Clamp><Glycohemoglobin A><Glycosylated hemoglobin A><Grant><Hb A1><Hb A1a+b><Hb A1c><HbA1><HbA1c><Health><Hemoglobin A(1)><Hormonal><Hormones><Hospitals><Human><Human Resources><Humulin R><Hydroxyapatites><Hyperglycemia><Impaired cognition><Impairment><Individual><Induced DNA Alteration><Induced Mutation><Induced Sequence Alteration><Insulin><Insulin Resistance><Intermediary Metabolism><Investments><Jewish><Journals><Judaism><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Laboratories><Learning><Letters><Literature><Magazine><Manpower><Manuscripts><Measures><Medicine><Metabolic><Metabolic Processes><Metabolic Studies><Metabolism><Metabolism Studies><Mice><Mice Mammals><Minerals><Modern Man><Morphology><Mouse Strains><Murine><Mus><Muscle><Muscle Tissue><NIH><National Institutes of Health><Nature><Neurologic><Neurological><Novolin R><Null Mouse><Osteocalcin><Patients><Pediatric Hospitals><Peer Review><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phenotype><Physiology><Population><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Production><Property><Protein Modification><Proteins><Publishing><Quarantine><Quetelet index><Rat><Rats Mammals><Rattus><Recombinants><Regular Insulin><Reporting><Reproducibility><Reproduction><Reproductive Biology><Research><Research Resources><Resources><Risk><Role><Science><Societies><Sperm Count><Sperm Count Procedure><Sperm Numbers><Testicles><Testis><The Jackson Laboratory><Therapeutic><Therapeutic Agents><Therapeutic Hormone><Translating><United States National Institutes of Health><Universities><Validation><Vitamin K><Vitamin K-Dependent Bone Protein><Vitamin K-Dependent Calcium-Binding Protein><Work><age associated muscle atrophy><age-associated decline in muscle><age-associated muscle decline><age-associated muscle deterioration><age-associated muscle loss><age-associated muscle wasting><age-related decline in muscle><age-related muscle decline><age-related muscle deterioration><age-related muscle loss><age-related muscle wasting><bio-markers><biologic><biologic marker><biomarker><biphosphonate><bisphosphonate><bone><bone mass><bone strength><brain deformity><brain malformation><cognitive dysfunction><cognitive loss><cohort><college><collegiate><conflict resolution><congenital brain anomaly><congenital brain deformity><developmental><diabetes><diets><diphosphonate><experiment><experimental research><experimental study><experiments><fascinate><fighting><follower of religion Jewish><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><glucose metabolism><glucose tolerance><hemoglobin A1c><hyperglycemic><inhibitor><insulin resistant><insulin tolerance><isolation/quarantine><kids><loss of function><loss of function mutation><male fertility><medical college><medical schools><metabolic abnormality assessment><metabolic phenotype><metabotype><microbiome><muscle bulk><muscle form><muscle mass><muscular><nano indentation><nanoindentation><novel><personnel><pharmaceutical><phenotypic data><programs><protein function><reproductive><reproductive hormone><response><school of medicine><skeletal><social role><validations><whole genome association analysis><whole genome association studies><whole genome association study><youngster>