Dataset Information

Multiscale Characterization of Embryonic Long Bone Mineralization in Mice.

ABSTRACT: Long bone mineralization occurs through endochondral ossification, where a cartilage template mineralizes into bone-like tissue with a hierarchical organization from the whole bone-scale down to sub-nano scale. Whereas this process has been extensively studied at the larger length scales, it remains unexplored at some of the smaller length scales. In this study, the changes in morphology, composition, and structure during embryonic mineralization of murine humeri are investigated using a range of high-resolution synchrotron-based imaging techniques at several length scales. With micro- and nanometer spatial resolution, the deposition of elements and the shaping of mineral platelets are followed. Rapid mineralization of the humeri occurs over approximately four days, where mineral to matrix ratio and calcium content in the most mineralized zone reach adult values shortly before birth. Interestingly, zinc is consistently found to be localized at the sites of ongoing new mineralization. The mineral platelets in the most recently mineralized regions are thicker, longer, narrower, and less aligned compared to those further into the mineralized region. In summary, this study demonstrates a specific spatial distribution of zinc, with highest concentration where new mineral is being deposited and that the newly formed mineral platelets undergo slight reshaping and reorganization during embryonic development.

SUBMITTER: Silva Barreto I

PROVIDER: S-EPMC7610310 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Multiscale Characterization of Embryonic Long Bone Mineralization in Mice.

Silva Barreto Isabella I Le Cann Sophie S Ahmed Saima S Sotiriou Vivien V Turunen Mikael J MJ Johansson Ulf U Rodriguez-Fernandez Angel A Grünewald Tilman A TA Liebi Marianne M Nowlan Niamh C NC Isaksson Hanna H

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200924 21

Long bone mineralization occurs through endochondral ossification, where a cartilage template mineralizes into bone-like tissue with a hierarchical organization from the whole bone-scale down to sub-nano scale. Whereas this process has been extensively studied at the larger length scales, it remains unexplored at some of the smaller length scales. In this study, the changes in morphology, composition, and structure during embryonic mineralization of murine humeri are investigated using a range o ...[more]

PMID: 33173750

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Project description:Excessive FGF23 has been identified as a pivotal phosphaturic factor leading to renal phosphate-wasting and the subsequent development of rickets and osteomalacia. In contrast, loss of FGF23 in mice (Fgf23(-/-) ) leads to high serum phosphate, calcium, and 1,25-vitamin D levels, resulting in early lethality attributable to severe ectopic soft-tissue calcifications and organ failure. Paradoxically, Fgf23(-/-) mice exhibit a severe defect in skeletal mineralization despite high levels of systemic mineral ions and abundant ectopic mineralization, an abnormality that remains largely unexplained. Through use of in situ hybridization, immunohistochemistry, and immunogold labeling coupled with electron microscopy of bone samples, we discovered that expression and accumulation of osteopontin (Opn/OPN) was markedly increased in Fgf23(-/-) mice. These results were confirmed by qPCR analyses of Fgf23(-/-) bones and ELISA measurements of serum OPN. To investigate whether elevated OPN levels were contributing to the bone mineralization defect in Fgf23(-/-) mice, we generated Fgf23(-/-) /Opn(-/-) double-knockout mice (DKO). Biochemical analyses showed that the hypercalcemia and hyperphosphatemia observed in Fgf23(-/-) mice remained unchanged in DKO mice; however, micro-computed tomography (µCT) and histomorphometric analyses showed a significant improvement in total mineralized bone volume. The severe osteoidosis was markedly reduced and a normal mineral apposition rate was present in DKO mice, indicating that increased OPN levels in Fgf23(-/-) mice are at least in part responsible for the osteomalacia. Moreover, the increased OPN levels were significantly decreased upon lowering serum phosphate by feeding a low-phosphate diet or after deletion of NaPi2a, indicating that phosphate levels contribute in part to the high OPN levels in Fgf23(-/-) mice. In summary, our results suggest that increased OPN is an important pathogenic factor mediating the mineralization defect and the alterations in bone metabolism observed in Fgf23(-/-) bones.

Dataset Information

Multiscale Characterization of Embryonic Long Bone Mineralization in Mice.

Publications

Multiscale Characterization of Embryonic Long Bone Mineralization in Mice.

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