Independent validation of experimental results requires timely and unrestricted access to animal models and reagents

Diegel, Cassandra R.; Hann, Steven; Ayturk, Ugur M.; Hu, Jennifer C. W.; Lim, Kyung-Eun; Droscha, Casey J.; Madaj, Zachary; Foxa, Gabrielle E.; Izaguirre, Isaac; Vivarium, Vai; Core, Transgenics; Robling, Alexander G.; Warman, Matthew L.; Williams, Bart O.

doi:10.1371/journal.pgen.1008940

Cited by 3 publications

(2 citation statements)

References 14 publications

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“…Why the Ocn −/− mouse line in the 129Sv;C57BL/6J mixed genetic background generated by Karsenty’s group exhibited impaired glucose metabolism needs to be investigated [ 58 , 59 ]. As there are inherent differences in glucose metabolism between 129 and C57BL/6 mouse lines [ 60 , 61 , 62 , 63 , 64 , 65 ], it is important to analyze the mice in a pure genetic background to reduce the variation in the data.…”

Section: Ocn and Glucose Metabolismmentioning

confidence: 99%

Functions of Osteocalcin in Bone, Pancreas, Testis, and Muscle

Komori

2020

IJMS

206

108

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Osteocalcin (Ocn), which is specifically produced by osteoblasts, and is the most abundant non-collagenous protein in bone, was demonstrated to inhibit bone formation and function as a hormone, which regulates glucose metabolism in the pancreas, testosterone synthesis in the testis, and muscle mass, based on the phenotype of Ocn−/− mice by Karsenty’s group. Recently, Ocn−/− mice were newly generated by two groups independently. Bone strength is determined by bone quantity and quality. The new Ocn−/− mice revealed that Ocn is not involved in the regulation of bone formation and bone quantity, but that Ocn regulates bone quality by aligning biological apatite (BAp) parallel to the collagen fibrils. Moreover, glucose metabolism, testosterone synthesis and spermatogenesis, and muscle mass were normal in the new Ocn−/− mice. Thus, the function of Ocn is the adjustment of growth orientation of BAp parallel to the collagen fibrils, which is important for bone strength to the loading direction of the long bone. However, Ocn does not play a role as a hormone in the pancreas, testis, and muscle. Clinically, serum Ocn is a marker for bone formation, and exercise increases bone formation and improves glucose metabolism, making a connection between Ocn and glucose metabolism.

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Section: Ocn and Glucose Metabolismmentioning

confidence: 99%

Functions of Osteocalcin in Bone, Pancreas, Testis, and Muscle

Komori

2020

IJMS

206

108

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“…Beyond some questions about the role of osteocalcin in bone, different potential roles of osteocalcin as an endocrine factor will be discussed below in detail. At present, additional work is needed to clarify this active controversy (42)(43)(44)(45). Potential future strategies that could be considered to address this controversy might include a blinded, side-by-side comparison of the 3 different osteocalcin-null models with appropriate age-and sex-matched littermate controls.…”

Section: Osteocalcin In Skeletal Developmentmentioning

confidence: 99%

Sclerostin and Osteocalcin: Candidate Bone-Produced Hormones

2021

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In addition to its structural role, the skeleton serves as an endocrine organ that controls mineral metabolism and energy homeostasis. Three major cell types in bone - osteoblasts, osteoclasts, and osteocytes – dynamically form and maintain bone and secrete factors with systemic activity. Osteocalcin, an osteoblast-derived factor initially described as a matrix protein that regulates bone mineralization, has been suggested to be an osteoblast-derived endocrine hormone that regulates multiple target organs including pancreas, liver, muscle, adipose, testes, and the central and peripheral nervous system. Sclerostin is predominantly produced by osteocytes, and is best known as a paracrine-acting regulator of WNT signaling and activity of osteoblasts and osteoclasts on bone surfaces. In addition to this important paracrine role for sclerostin within bone, sclerostin protein has been noted to act at a distance to regulate adipocytes, energy homeostasis, and mineral metabolism in the kidney. In this article, we aim to bring together evidence supporting an endocrine function for sclerostin and osteocalcin, and discuss recent controversies regarding the proposed role of osteocalcin outside of bone. We summarize the current state of knowledge on animal models and human physiology related to the multiple functions of these bone-derived factors. Finally, we highlight areas in which future research is expected to yield additional insights into the biology of osteocalcin and sclerostin.

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Explaining Divergent Observations Regarding Osteocalcin/GPRC6A Endocrine Signaling

Nishimoto

Quarles

2021

Endocrinology

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A new schema proposes that the bone-derived osteocalcin (Ocn) peptide hormone activates the G- protein coupled receptor GPRC6A to directly regulate glucose and fat metabolism in liver, muscle and fat, and to stimulate the release of metabolism-regulating hormones, including insulin, fibroblast growth factor 21, glucagon-like peptide 1, testosterone and interleukin 6. Ocn/GPRC6A activation has also been implicated in cancer progression. GPRC6Ais activated by cations, amino acids and testosterone. The multi-ligand specificity, the regulation of energy metabolism in diverse tissues and the coordinated release of metabolically active hormones make the GPRC6A endocrine networks unique. Recently the significance of Ocn/GPRCA have been questioned. There is a lack of metabolic abnormalities in newly created genetically engineered Ocn- and Gprc6a-deficient mouse models. There are also paradoxical observations that GPRC6A may function as a tumor suppressor. In addition, discordant published studies have cast doubt on the function of the most prevalent uniquely human GPRC6A-KGKY polymorphism. Explanations for these divergent findings are elusive. We provide evidence that the metabolic susceptibility of genetically engineered Ocn- and Gprc6a-deficient mice is influenced by environmental challenges and genetic differences in mouse strains. In addition, the GPRC6A-KGKY polymorphism appears to be a gain-of-function variant. Finally, alternatively spliced isoforms of GPRC6A may alter ligand specificity and signaling that modulate oncogenic effects. Thus, genetic, post-translational and environmental factors likely account for the variable results regarding the functions of GPRC6A in animal models. Pending additional information, GPRC6A should remain a potential therapeutic target for regulating energy and fat metabolism, hormone production, and cancer progression.

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Independent validation of experimental results requires timely and unrestricted access to animal models and reagents

Abstract: Independent validation of experimental results requires timely and unrestricted access to animal models and reagents. PLoS Genet 16(6): e1008940.

Cited by 3 publications

References 14 publications

Functions of Osteocalcin in Bone, Pancreas, Testis, and Muscle

Functions of Osteocalcin in Bone, Pancreas, Testis, and Muscle

Sclerostin and Osteocalcin: Candidate Bone-Produced Hormones

Explaining Divergent Observations Regarding Osteocalcin/GPRC6A Endocrine Signaling

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