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Journal of the Royal Society, Interface Oct 2016Polar and charged amino acids (AAs) are heavily expressed in non-collagenous proteins (NCPs), and are involved in hydroxyapatite (HA) mineralization in bone. Here, we... (Review)
Review
Polar and charged amino acids (AAs) are heavily expressed in non-collagenous proteins (NCPs), and are involved in hydroxyapatite (HA) mineralization in bone. Here, we review what is known on the effect of single AAs on HA precipitation. Negatively charged AAs, such as aspartic acid, glutamic acid (Glu) and phosphoserine are largely expressed in NCPs and play a critical role in controlling HA nucleation and growth. Positively charged ones such as arginine (Arg) or lysine (Lys) are heavily involved in HA nucleation within extracellular matrix proteins such as collagen. Glu, Arg and Lys intake can also increase bone mineral density by stimulating growth hormone production. In vitro studies suggest that the role of AAs in controlling HA precipitation is affected by their mobility. While dissolved AAs are able to inhibit HA precipitation and growth by chelating Ca and PO ions or binding to nuclei of calcium phosphate and preventing their further growth, AAs bound to surfaces can promote HA precipitation by attracting Ca and PO ions and increasing the local supersaturation. Overall, the effect of AAs on HA precipitation is worth being investigated more, especially under conditions closer to the physiological ones, where the presence of other factors such as collagen, mineralization inhibitors, and cells heavily influences HA precipitation. A deeper understanding of the role of AAs in HA mineralization will increase our fundamental knowledge related to bone formation, and could lead to new therapies to improve bone regeneration in damaged tissues or cure pathological diseases caused by excessive mineralization in tissues such as cartilage, blood vessels and cardiac valves.
Topics: Amino Acids; Animals; Bone Density; Calcification, Physiologic; Durapatite; Extracellular Matrix; Humans; Models, Biological
PubMed: 27707904
DOI: 10.1098/rsif.2016.0462 -
Nature Biomedical Engineering Nov 2023In patients with breast cancer, lower bone mineral density increases the risk of bone metastasis. Although the relationship between bone-matrix mineralization and...
In patients with breast cancer, lower bone mineral density increases the risk of bone metastasis. Although the relationship between bone-matrix mineralization and tumour-cell phenotype in breast cancer is not well understood, mineralization-induced rigidity is thought to drive metastatic progression via increased cell-adhesion forces. Here, by using collagen-based matrices with adjustable intrafibrillar mineralization, we show that, unexpectedly, matrix mineralization dampens integrin-mediated mechanosignalling and induces a less proliferative stem-cell-like phenotype in breast cancer cells. In mice with xenografted decellularized physiological bone matrices seeded with human breast tumour cells, the presence of bone mineral reduced tumour growth and upregulated a gene-expression signature that is associated with longer metastasis-free survival in patients with breast cancer. Our findings suggest that bone-matrix changes in osteogenic niches regulate metastatic progression in breast cancer and that in vitro models of bone metastasis should integrate organic and inorganic matrix components to mimic physiological and pathologic mineralization.
Topics: Humans; Mice; Animals; Female; Bone Matrix; Integrins; Breast Neoplasms; Calcification, Physiologic; Collagen; Mammary Neoplasms, Animal; Calcinosis
PubMed: 37550422
DOI: 10.1038/s41551-023-01077-3 -
Scientific Reports Jan 2018Tough natural nanocomposites like bone, nacre and sea sponges contain within their hierarchy, a mineral (phosphate, silicate or carbonate) phase that interacts with an...
Tough natural nanocomposites like bone, nacre and sea sponges contain within their hierarchy, a mineral (phosphate, silicate or carbonate) phase that interacts with an organic phase. In bone, the role of mineral ultrastructure (organization, morphology, composition) is crucial to the mechanical and biological properties of the tissue. Better understanding of mineral interaction with the organic matrix, in particular non-collagenous proteins, osteocalcin (OC) and osteopontin (OPN), can lead to better design of biomimetic materials. Using small angle x-ray scattering (SAXS) and wavelength dispersive spectroscopy (WDS) on single (OC and OPN) and double (OC-OPN) genetic knockout mice bones, we demonstrate that both osteocalcin and osteopontin have specific roles in the biomolecular regulation of mineral in bone and together they are major determinants of the quality of bone mineral. Specifically, for the first time, we show that proteins osteocalcin and osteopontin regulate bone mineral crystal size and organization in a codependent manner, while they independently determine crystal shape. We found that OC is more dominant in the regulation of the physical properties of bone mineral, while OPN is more dominant in the regulation of the mineral composition.
Topics: Animals; Bone and Bones; Calcification, Physiologic; Genotype; Mice; Mice, Knockout; Minerals; Models, Biological; Osteocalcin; Osteopontin; Scattering, Small Angle; Trace Elements; X-Ray Diffraction
PubMed: 29352125
DOI: 10.1038/s41598-018-19253-w -
Journal of Structural Biology Dec 2021Uptake and concentration of inorganic ions are part of the complex cellular processes required for cell homeostasis, as well as for mineral formation by organisms. These... (Review)
Review
Uptake and concentration of inorganic ions are part of the complex cellular processes required for cell homeostasis, as well as for mineral formation by organisms. These ion transport mechanisms include distinct cellular compartments and chemical phases that play various roles in the physiology of organisms. Here, the prominent cases of dense ion pools in unicellular organisms are briefly reviewed. The specific observations that were reported for different organisms are consolidated into a wide perspective that emphasizes general traits. It is suggested that the intracellular ion pools can be divided into three types: a high cytoplasmic concentration, a labile storage compartment that hosts dense ion-rich phases, and a mineral-forming compartment in which a stable long-lived structure is formed. Recently, many labile pools were identified in various organisms using advanced techniques, bringing many new questions about their possible roles in the formation of the stable mineralized structures.
Topics: Bacteria; Biomineralization; Calcification, Physiologic; Homeostasis; Intracellular Space; Ion Transport; Ions; Minerals; Organelles; Phytoplankton
PubMed: 34740781
DOI: 10.1016/j.jsb.2021.107807 -
Annals of African Medicine 2017Resorptive cells are responsible for the resorption of mineralized matrix of hard tissues. Bone-resorbing cells are called osteoclasts; however, they can resorb... (Review)
Review
Resorptive cells are responsible for the resorption of mineralized matrix of hard tissues. Bone-resorbing cells are called osteoclasts; however, they can resorb mineralized dental tissues or calcified cartilage and then they are called odontoclasts and chondroclasts, respectively. Resorptive cells form when mononuclear precursors derived from a monocyte-macrophage cell lineage are attracted to certain mineralized surfaces and subsequently fuse and adhere onto them for exerting their resorbing activity. These cells are responsible for degradation of calcified extracellular matrix composed of organic molecules and hydroxyapatite. The activity of these cells can be observed in both physiological and pathological processes throughout life and their activity is mainly required in bone turnover and growth, spontaneous and induced (orthodontic) tooth movement, tooth eruption, and bone fracture healing, as well as in pathological conditions such as osteoporosis, osteoarthritis, and bone metastasis. In addition, they are responsible for daily control of calcium homeostasis. Clastic cells also resorb the primary teeth for shedding before the permanent teeth erupt into the oral cavity.
Topics: Bone Diseases; Bone Resorption; Calcification, Physiologic; Humans; Odontogenesis; Osteoclasts; Tooth, Deciduous
PubMed: 28469115
DOI: 10.4103/aam.aam_97_16 -
Clinical Nephrology Mar 2016The aim of this study was to evaluate the associations between bone histomorphometry and bone volume measured by dual-energy X-ray absorptiometry (DXA) in wait-listed... (Comparative Study)
Comparative Study Observational Study
AIMS
The aim of this study was to evaluate the associations between bone histomorphometry and bone volume measured by dual-energy X-ray absorptiometry (DXA) in wait-listed dialysis patients. Further, the circulating markers of mineral metabolism and bone turnover were compared.
MATERIAL AND METHODS
Bone biopsies were performed on 61 wait-listed dialysis patients. Plasma samples were obtained for indicators of mineral metabolism and bone turnover. Bone mineral density (BMD) was determined by DXA and bone histomorphometry was performed.
RESULTS
Bone histomorphometry could be determined in 52 patients (72% men, 54% on hemodialysis and median dialysis vintage 18 months). Adynamic bone disease was present in 21% of patients and 4% had osteomalacia. High turnover bone disease (mixed uremic osteodystrophy and osteitis fibrosa) was observed in 48% of patients (17% and 31%, respectively). 10% of patients had normal bone histomorphometry while 17% had mild osteitis fibrosa. Mineralization defect was found in 33% of patients. There was a strong correlation between femoral neck (FN) T-score and histologically measured cancellous bone volume (p = 0.004), FN T-score having a good negative predictive value for low cancellous bone volume. Plasma osteocalcin levels were significantly higher in the high-turnover group and lower in the mineralization defect group (p = 0.014 and p = 0.02, respectively).
CONCLUSIONS
Our study confirms the high frequency of abnormal bone histology in wait-listed dialysis patients. Low bone turnover was less common than previously reported. Noninvasive markers had a limited value for assessing bone histology, whereas femoral BMD reflected bone volume well.
Topics: Absorptiometry, Photon; Adult; Alkaline Phosphatase; Biomarkers; Biopsy; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Bone and Bones; Calcification, Physiologic; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Femur; Humans; Male; Middle Aged; Minerals; Osteitis Fibrosa Cystica; Osteocalcin; Osteomalacia; Parathyroid Hormone; Renal Dialysis; Waiting Lists
PubMed: 26833298
DOI: 10.5414/CN108709 -
Seminars in Cell & Developmental Biology Oct 2015Mineral makes up more than half the volume of bone, but its spatial and structural relationship to collagen and other proteins is still a matter of debate. Due to the... (Review)
Review
Mineral makes up more than half the volume of bone, but its spatial and structural relationship to collagen and other proteins is still a matter of debate. Due to the nanometer-size of bone crystals this matter can be resolved only with transmission electron microscope (TEM) images. Using sections cut with an ultramicrotome, previous investigators determined most mineral lies in the 40nm wide gap zone in collagen fibrils. Using less invasive sectioning methods (ion milling and focused ion beam [FIB]) reveals that most mineral is extrafibrillar, occurring in the form of mineral lamellae, polycrystalline plates 300nm or more long, packed around collagen fibrils in stacks of four or more lamellae <1nm apart. While Ca and P also occur in the gap zone, they do not appear to be in the form of well-crystallized apatite. This new model for bone ultrastructure resolves outstanding problems presented by the previous model.
Topics: Animals; Bone and Bones; Calcification, Physiologic; Collagen; Crystallization; Humans; Microscopy, Electron, Transmission; Minerals; Models, Structural
PubMed: 26165821
DOI: 10.1016/j.semcdb.2015.06.008 -
Journal of the Mechanical Behavior of... Dec 2015In this paper, we review the hierarchical structure and the resulting elastic properties of mineralized tendons as obtained by various multiscale experimental and... (Review)
Review
In this paper, we review the hierarchical structure and the resulting elastic properties of mineralized tendons as obtained by various multiscale experimental and computational methods spanning from nano- to macroscale. The mechanical properties of mineralized collagen fibres are important to understand the mechanics of hard tissues constituted by complex arrangements of these fibres, like in human lamellar bone. The uniaxial mineralized collagen fibre array naturally occurring in avian tendons is a well studied model tissue for investigating various stages of tissue mineralization and the corresponding elastic properties. Some avian tendons mineralize with maturation, which results in a graded structure containing two zones of distinct morphology, circumferential and interstitial. These zones exhibit different amounts of mineral, collagen, pores and a different mineral distribution between collagen fibrillar and extrafibrillar space that lead to distinct elastic properties. Mineralized tendon cells have two phenotypes: elongated tenocytes placed between fibres in the circumferential zone and cuboidal cells with lower aspect ratios in the interstitial zone. Interestingly some regions of avian tendons seem to be predestined to mineralization, which is exhibited as specific collagen cross-linking patterns as well as distribution of minor tendon constituents (like proteoglycans) and loss of collagen crimp. Results of investigations in naturally mineralizing avian tendons may be useful in understanding the pathological mineralization occurring in some human tendons.
Topics: Animals; Biomechanical Phenomena; Humans; Mechanical Phenomena; Minerals; Structure-Activity Relationship; Tendons
PubMed: 25922092
DOI: 10.1016/j.jmbbm.2015.03.013 -
Journal of Bone and Mineral Research :... Aug 2021Auditory ossicles in the middle ear and bony labyrinth of the inner ear are highly mineralized in adult mammals. Cellular mechanisms underlying formation of dense bone...
Auditory ossicles in the middle ear and bony labyrinth of the inner ear are highly mineralized in adult mammals. Cellular mechanisms underlying formation of dense bone during development are unknown. Here, we found that osteoblast-like cells synthesizing highly mineralized hearing-related bones produce both type I and type II collagens as the bone matrix, while conventional osteoblasts and chondrocytes primarily produce type I and type II collagens, respectively. Furthermore, these osteoblast-like cells were not labeled in a "conventional osteoblast"-specific green fluorescent protein (GFP) mouse line. Type II collagen-producing osteoblast-like cells were not chondrocytes as they express osteocalcin, localize along alizarin-labeled osteoid, and form osteocyte lacunae and canaliculi, as do conventional osteoblasts. Auditory ossicles and the bony labyrinth exhibit not only higher bone matrix mineralization but also a higher degree of apatite orientation than do long bones. Therefore, we conclude that these type II collagen-producing hypermineralizing osteoblasts (termed here auditory osteoblasts) represent a new osteoblast subtype. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Animals; Bone and Bones; Calcification, Physiologic; Hearing; Mice; Osteoblasts; Osteocalcin
PubMed: 33905562
DOI: 10.1002/jbmr.4320 -
Bone Aug 2017Osteopontin (OPN) belongs to the SIBLING family (Small, Integrin-Binding LIgand N-linked Glycoproteins) of mineral-binding matrix proteins found in bones and teeth. OPN...
Osteopontin (OPN) belongs to the SIBLING family (Small, Integrin-Binding LIgand N-linked Glycoproteins) of mineral-binding matrix proteins found in bones and teeth. OPN is a well-known inhibitor of matrix mineralization, and enzymatic modification of OPN can affect this inhibitory function. In bone, OPN exists both as a monomer and as a high-molecular-weight polymer - the latter is formed by transglutaminase-mediated crosslinking of glutamine and lysine residues in OPN to create homotypic protein assemblies. OPN can be covalently crosslinked by transglutaminase 2 (TG2) and Factor XIII-A. Polymeric OPN has increased binding to collagen and promotes osteoblast adhesion, but despite these initial observations, its role in mineralization is not clear. In this study, we investigated the effect of polymerized OPN on mineralization using a hydroxyapatite crystal growth assay and mineralizing MC3T3-E1 osteoblast cultures. In the cultures, endogenous polymeric OPN was detected after mineralization occurred. In cell-free conditions, TG2 was used to crosslink bovine OPN into its polymeric form, and atomic force microscopy and dynamic light scattering revealed variably-sized, large branched aggregates ranging across hundreds of nanometers. These OPN polymers inhibited the growth of hydroxyapatite crystals in solution at concentrations similar to monomeric OPN, although the crosslinking slightly reduced its inhibitory potency. When added to MC3T3-E1 osteoblast cultures, this exogenous polymeric OPN essentially did not inhibit mineralization when given during the later mineralization stages of culture; however, cultures treated early and then continuously with polymeric OPN throughout both the matrix assembly and mineral deposition stages showed reduced mineralization. Immunoblotting of protein extracts from these continuously treated cultures revealed exogenous OPN polymers incorporated into mature matrix that had not yet mineralized. These results suggest that in bone, the increased size and branched structure of crosslinked inhibitory polymeric OPN near the mineralization front could hinder it from accessing focal mineralization sites in the dense collagen-rich matrix, suggesting that OPN-crosslinking into polymers may represent a way to fine-tune the inhibitory potency of OPN on bone mineralization.
Topics: Animals; Calcification, Physiologic; Cell Line; Cell Survival; Durapatite; Dynamic Light Scattering; GTP-Binding Proteins; Immunoblotting; Microscopy, Atomic Force; Osteoblasts; Osteopontin; Polymers; Protein Glutamine gamma Glutamyltransferase 2; Transglutaminases
PubMed: 28428079
DOI: 10.1016/j.bone.2017.04.007