Bone mineralization proceeds through intracellular calcium phosphate loaded vesicles: A cryo-electron microscopy study
Abstract
Bone is the most widespread mineralized tissue in vertebrates and its formation is orchestrated by specialized cells - the osteoblasts. Crystalline carbonated hydroxyapatite, an inorganic calcium phosphate mineral, constitutes a substantial fraction of mature bone tissue. Yet key aspects of the mineral formation mechanism, transport pathways and deposition in the extracellular matrix remain unidentified. Using cryo-electron microscopy on native frozen-hydrated tissues we show that during mineralization of developing mouse calvaria and long bones, bone-lining cells concentrate membrane-bound mineral granules within intracellular vesicles. Elemental analysis and electron diffraction show that the intracellular mineral granules consist of disordered calcium phosphate, a highly metastable phase and a potential precursor of carbonated hydroxyapatite. The intracellular mineral contains considerably less calcium than expected for synthetic amorphous calcium phosphate, suggesting the presence of a cellular mechanism by which phosphate entities are first formed and thereafter gradually sequester calcium within the vesicles. We thus demonstrate that in vivo osteoblasts actively produce disordered mineral packets within intracellular vesicles for mineralization of the extracellular developing bone tissue. The use of a highly disordered precursor mineral phase that later crystallizes within an extracellular matrix is a strategy employed in the formation of fish fin bones and by various invertebrate phyla. This therefore appears to be a widespread strategy used by many animal phyla, including vertebrates.
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Ca/P ratios of granules within undecalcified calcifying cartilage prepared under anhydrous conditions measured 0.8-1.1, and the same ratio measured in mineralizing murine bone granules in cryo conditions was 0.75 ± 0.22.
“Ca/P ratios of granules within undecalcified calcifying cartilage prepared under anhydrous conditions measured 0.8–1.1 [123], and the same ratio measured in mineralizing murine bone granules in cryo conditions was 0.75 ± 0.22 [133].”
From A Review of Phosphate Mineral Nucleation in Biology and Geobiology (2013) · cites this paper as [133]
Cryo-EM and HPF-FS preparation have recently provided evidence of a secretory process for bone mineralization.
“Cryo-EM and HPF-FS preparation have recently provided evidence of a secretory process for bone mineralization [131, 133, 154, 155].”
From A Review of Phosphate Mineral Nucleation in Biology and Geobiology (2013) · cites this paper as [133]
These nano-spheres were identified within preosteoblasts, osteoblasts, and osteocytes.
“These nano-spheres were identified within preosteoblasts, osteoblasts, and osteocytes [133].”
From A Review of Phosphate Mineral Nucleation in Biology and Geobiology (2013) · cites this paper as [133]
Mahamid et al. imaged intracellular, membrane-bound, 80-nm-diameter Ca- and P-rich globules, which in turn are composed of smaller 10-nm spheres, in mineralizing embryonic and up to postnatal day 2 murine bones.
“Mahamid et al. [133] imaged intracellular, membrane-bound, 80-nm-diameter Ca- and P-rich globules, which in turn are composed of smaller 10-nm spheres in mineralizing embryonic and up to postnatal day 2 murine bones.”
From A Review of Phosphate Mineral Nucleation in Biology and Geobiology (2013) · cites this paper as [133]
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- Authors
- Mahamid, J., Sharir, A., Gur, D., Zelzer, E., Addadi, L., & Weiner, S.
- Affiliations
- Weizmann Institute of Science (IL)
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Mahamid, Julia
- Venue
- Journal of Structural Biology
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 174
- Issue
- 3
- Pages
- 527-535
- ISSN
- 1047-8477 (ISSN-L)
- OpenAlex
- W2030345505
- Cited by
- 272
- References
- 46
- Citations by year
- 2026: 8 · 2025: 21 · 2024: 11 · 2023: 19 · 2022: 9 · 2021: 23 · 2020: 19 · 2019: 26 · 2018: 25 · 2017: 15 · 2016: 27 · 2015: 20 · 2014: 20 · 2013: 14 · 2012: 12
- FWCI
- 12.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Structural Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Kimmelman Center for Biomolecular Structure and Assembly, Weizmann Institute
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Alkaline Phosphatase Research Studies
- Physical Sciences › Materials Science › Biomaterials › Calcium Carbonate Crystallization and Inhibition
- Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
- Keywords
- bone mineralization, osteoblasts, intracellular vesicles, amorphous calcium phosphate, hydroxyapatite, bone matrix, long bones
- MeSH terms
- Animals, Bone and Bones, Calcification, Physiologic, Calcium Phosphates, Cytoplasmic Granules, Embryo, Mammalian, Fishes, Mice, Inbred C57BL, Skull, Tomography, X-Ray Computed, Durapatite, Cryoelectron Microscopy, Mice
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