Bone mineralization proceeds through intracellular calcium phosphate loaded vesicles: A cryo-electron microscopy study

Mahamid, Julia; Sharir, Amnon; Gur, Dvir; Zelzer, Elazar; Addadi, Lia; Weiner, Steve

doi:10.1016/j.jsb.2011.03.014

Cited by 235 publications

(215 citation statements)

References 36 publications

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“…It has previously been shown that the initial step of in vivo mineralization requires a highly amorphous precursor calcium phosphate that later matures into HA within the extracellular matrix (Mahamid et al 2011), and a similar finding was observed in tooth enamel (Holt 1997). Collagen can be mineralized with HA by OPN CPN (Rodriguez et al, 2014).…”

Section: Resultsmentioning

confidence: 63%

Structural studies of hydrated samples of amorphous calcium phosphate and phosphoprotein nanoclusters

et al. 2016

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There are abundant examples of nanoclusters and inorganic microcrystals in biology.Their study under physiologically relevant conditions remains challenging due to their instability, the requirements of sample preparation and other intrinsic limitations of the techniques used. Advantages of using neutron diffraction and contrast matching to characterize biomaterials are highlighted in this article. We have applied these methods and complementary techniques to search for long-range order within nanoclusters of calcium phosphate sequestered by bovine phosphopeptides, derived from osteopontin or casein. Hydrated and dried samples with different nanocluster radii were analyzed and compared to samples of known calcium phosphate phases. The absence of a distinct diffraction pattern from the nanoclusters is consistent with the presence of amorphous calcium phosphate structure.

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Section: Resultsmentioning

confidence: 63%

Structural studies of hydrated samples of amorphous calcium phosphate and phosphoprotein nanoclusters

et al. 2016

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“…Protective mechanisms are thus in place by which cells can urgently decrease dangerously high levels of cytosolic calcium 3 by the budding off of calcium-rich vesicles into the extracellular matrix. As a result of calcium sequestration by proteins, PPi and polyPi, and following Ostwald's rule of phase transformation (in an environment of high saturation the first forming phase is likely to be metastable), extracellular vesicles contain disordered calcium phosphate 43 . Of note, that biomineralization proceeds via an amorphous pathway is well recognized in the realm of invertebrates who produce their skeletons of calcium carbonate 44 .…”

Section: Compartmentalization Of Calcium and Phosphate Ionsmentioning

confidence: 99%

“…Despite the high elemental density of the vesicles loaded with disordered mineral, their Ca/Pi ratio was lower than that found in mature bone mineral and in stoichiometric hydroxyapatite. A feasible explanation is that the phosphate-rich phase (possibly polyPi) forms first and sequesters intracellular calcium which is otherwise toxic to cells 43 . An in vitro study of an osteoblastic culture showed that analogous intracellular granules containing amorphous calcium phosphate are associated with mitochondria 46 .…”

Section: Compartmentalization Of Calcium and Phosphate Ionsmentioning

confidence: 99%

“…For example, high-resolution electron microscopy imaging used today in the field of structural biology cannot be even thought of without the use of advanced cryo-preservation methods to keep molecules and cells in their pristine, hydrated native state, as opposed to the chemical fixation that is associated with dehydration and distortion of the sample 43,112,113 . Biomineralization is a multi-step process involving mineral-protein complexes and meta-stable compounds (such as amorphous calcium-phosphate), and therefore, arguably the most informative way to interrogate this in detail might be dynamic liquid-cell or atmospheric electron microscopy to provide analysis under more native aqueous conditions 113,114 .…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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A materials science vision of extracellular matrix mineralization

et al. 2016

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From an engineering perspective, skeletal tissues are remarkable structures in that they are lightweight, stiff and tough, yet produced at ambient conditions. The biomechanical success of skeletal tissues is largely attributable to the process of biomineralization -a tightly regulated, cell-driven formation of billions of inorganic nanocrystals formed from ions found abundantly in body fluids. In this Review, we discuss nature's strategies to produce and sustain appropriate biomechanical properties in mineralizing (by promotion of mineralization) and nonmineralizing (by inhibition of mineralization) tissues. We review how perturbations of biomineralization are controlled over a continuum which spans from the desirable (or defective in disease) mineralization of the skeleton, to pathological cardiovascular mineralization, and to mineralization of bioengineered constructs. A materials science vision of mineralization is presented with an emphasis on the micro-and nanostructure of mineralized tissues recently revealed by state-of-the-art analytical methods, and on how biomineralization-inspired designs are impacting the field of synthetic materials. Web summaryComplex mechanisms are at play in the biomineralization of skeletal tissues and in patholological calcification in the cardiovascular system. In this Review, the physiochemical and biomechanical properties of mineralized tissues, both physiologic and pathophysiologic, and analytical methods to elucidate their finer structure are discussed.

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“…For example, vesicular structures containing mineral precursors are involved in bone development and sea urchin spiculogenesis (Mahamid et al 2011;Vidavsky et al 2014). Although the effects of macromolecule-or vesicle-based confinement at different length scales on mineralization are not completely clear, some possible explanations for the distinct nucleation behavior are (1) a confinement size-dependent interplay between homogenous and heterogeneous nucleation (Woo et al 2007), (2) critical size constraints corresponding to crystal nuclei (or ion-associates) and related polymorph selectivity (Ha et al 2004), and (3) size constraint-driven thermodynamic crossovers in phase stability (Hamilton et al 2008;Navrotsky 2004;Raiteri and Gale 2010), as well as distinct solvent dynamics and physicochemical conditions in restricted environments and the bulk solvent (Brubach et al 2001;Moilanen et al 2007;.…”

Section: Crowded Solutions and Confinement: Impact On Nucleationmentioning

confidence: 99%

Mineralization and non-ideality: on nature’s foundry

Rao¹,

Cölfen

2016

Biophys Rev

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Understanding how ions, ion-clusters and particles behave in non-ideal environments is a fundamental question concerning planetary to atomic scales. For biomineralization phenomena wherein diverse inorganic and organic ingredients are present in biological media, attributing biomaterial composition and structure to the chemistry of singular additives may not provide a holistic view of the underlying mechanisms. Therefore, in this review, we specifically address the consequences of physico-chemical non-ideality on mineral formation. Influences of different forms of non-ideality such as macromolecular crowding, confinement and liquid-like organic phases on mineral nucleation and crystallization in biological environments are presented. Novel prospects for the additive-controlled nucleation and crystallization are accessible from this biophysical view. In this manner, we show that non-ideal conditions significantly affect the form, structure and composition of biogenic and biomimetic minerals.

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Bone mineralization proceeds through intracellular calcium phosphate loaded vesicles: A cryo-electron microscopy study

Cited by 235 publications

References 36 publications

Structural studies of hydrated samples of amorphous calcium phosphate and phosphoprotein nanoclusters

Structural studies of hydrated samples of amorphous calcium phosphate and phosphoprotein nanoclusters

A materials science vision of extracellular matrix mineralization

Mineralization and non-ideality: on nature’s foundry

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