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PubMed1993

Age and disease-related changes in the mineral of bone.

Bone mineralization changes with age and disease. The distribution of mineral particles in a given bone (mineralization profile) has been studied using density fractionation as well as microradiography and electron backscattering imaging. The biological determinant of mineralization is the rate of turnover. During rapid growth and periods of high remodeling, mineralization is shifted towards lower mineral density (hypomineralization). During aging and periods of low remodeling, mineralization is shifted towards higher mineral densities (hypermineralization). Chemicals can also influence the mineralization profile of bone. Fluoride induces hypermineralization by stabilizing the apatite lattice and reducing bone mineral solubility, whereas strontium induces hypomineralization by loosening the apatite lattice and increasing bone mineral solubility. Drugs such as bisphosphonates induce hypermineralization by inhibiting resorption and acting as crystal poison. Finally, mineralization can be impaired by defects as in rickets and osteomalacia or made excessive by continuous accretion of mineral without resorption as in osteopetrosis.

Absorptiometry, Photon↗
PubMed1991

Initiation and progression of mineralization of bone nodules formed in vitro: the role of alkaline phosphatase and organic phosphate.

Osteoid nodules form but do not mineralize in fetal rat calvaria cell cultures grown in alpha-minimal essential medium with 10% fetal bovine serum in the absence of Na beta-glycerophosphate (beta-GP). To study factors involved in the initiation and progression of mineralization, cultures were treated with beta-GP and radiolabelled with 0.1-0.2 microCi/ml 45Ca after nodules had formed (17-19 days in medium without beta-GP). Concentrations of beta-GP from 1 to 14 mM induced a dose-dependent increase in 45Ca uptake. 45Ca uptake was restricted to nodule-containing cultures and did not occur in cultures without nodules. Continuous labelling over 72 h compared with 2 h pulses over the same time period showed that little mineralization occurred over the first 8-12 h and that the rate of mineralization was maximal and constant after 24 h exposure to beta-GP. Calcium uptake from medium was slow during the first 12 h of beta-GP exposure but increased rapidly thereafter until the medium calcium concentration reached a steady state of between 0.5 and 0.6 mM. Measurement of calcium concentration in the medium after mineralization had been initiated (24 h after beta-GP exposure) showed a linear calcium uptake into nodules (r = 0.990) over a 7 h period at a rate of 9.2 micrograms calcium/h/culture. Initiation of mineralization was prevented by 100 microM levamisole, but not by 100 microM dexamisole. When 100 microM levamisole was added 24 h after mineralization had been initiated by the addition of beta-GP, the progression of mineralization was unaffected. Similarly, after mineralization had been initiated for 24 h by 10 mM beta-GP, mineralization continued independent of the presence of beta-GP. The data show that the initiation and progression of mineralization are separate phenomena and that organic phosphate and alkaline phosphatase play a crucial role in the initiation of mineralization but are not required for the continuation of mineralization of bone nodules.

Alkaline Phosphatase↗
PubMed1992

Inorganic phosphate added exogenously or released from beta-glycerophosphate initiates mineralization of osteoid nodules in vitro.

Rat calvaria (RC) cells grown in medium containing ascorbic acid form nodules of osteoid and cells. When 10 mM beta-Glycerophosphate (beta-GP) is added, the osteoid mineralizes in two phases: an initiation phase that is dependent upon alkaline phosphatase activity and a progression phase that proceeds independently of the activity of alkaline phosphatase and does not require added beta-GP (Bellows et al., Bone Miner 1991;14:27-40). The present experiments were performed to determine whether beta-GP is converted to inorganic phosphate (Pi) during the initiation phase of the mineralization process and whether increased Pi can replace beta-GP in the initiation phase. Measurements of Pi concentrations in the culture medium showed that during the first 8 h of the initiation phase of mineralization, 10 mM beta-GP was rapidly degraded resulting in Pi concentrations of 9-10 mM. The production rate of Pi from beta-GP was linear (r = 0.996) and the alkaline phosphatase activity in the same cultures indicated a potential for conversion of beta-GP to Pi that was greater than the actual conversion rate. The addition of 2-5 mM Pi in the absence of beta-GP also initiated mineralization. Mineralization initiated by either beta-GP or Pi progressed in the absence of added beta-GP or Pi. 100 microM Levamisole inhibited the initiation of beta-GP-induced mineralization and the conversion of beta-GP to Pi, but did not affect Pi-induced initiation of mineralization. The addition of 1-5 mM Pi to cultures in which mineralization had been initiated by 10 mM beta-GP had no significant effect on the progression phase of mineralization. Neither beta-BP nor Pi initiated 45Ca uptake in cultures without nodules (RC population I) and the histological appearance of the mineralized tissue in either phosphate source appeared identical. The present experiments show that beta-GP is rapidly and virtually completely degraded to Pi during the initiation phase of mineralization and that the addition of increased concentrations of Pi can replace beta-GP in the initiation phase of mineralization in the absence of non-specific 45Ca uptake or apparent cellular toxicity.

Alkaline Phosphatase↗
PubMed1998

Matrix mineralization in MC3T3-E1 cell cultures initiated by beta-glycerophosphate pulse.

MC3T3-E1 cells, grown in the presence of serum and ascorbate, express alkaline phosphatase and produce an extensive collagenous extracellular matrix that can be mineralized by the addition of beta-glycerophosphate (beta-GP). In the present work, we study the influence of concentration and duration of beta-GP treatment on the mineralization pattern in 4-week-old cell cultures. Amount and structure of mineral deposition were monitored by von Kossa staining, light, and electron microscopy, as well as small-angle X-ray scattering (SAXS) of unstained specimens. SAXS measures the total surface of the mineral phase and is therefore preferentially sensitive to very small crystals (typically <50 nm). It was used to determine the ratio (M) of small crystals to collagen matrix. A variety of mineralization patterns was observed to occur simultaneously, some associated with collagen within nodules or in deeper layers of the cultures and some independent of it. At a beta-GP concentration of 10 mmol, mineralization was initiated after about 24 h and continued to increase, irrespective of whether the high level of beta-GP was maintained or reduced to 2 mmol. With shorter pulses (<24 h), no significant mineralization was observed in the week following beta-GP pulse. With continuous treatment at 5 mmol beta-GP, the first signs of mineralization were detected 14 days after the beginning of treatment in the 4-week-old cultures, but no mineralization at all occurred at lower beta-GP concentrations. When cells were grown without ascorbic acid for 4 weeks, only two cell layers without collagen matrix were found. In these cultures, no mineralization detectable by SAXS could be induced with beta-GP. These data indicate that, in viable cells, high doses of beta-GP are essential for the nucleation of mineral crystals, but not for the progression of mineralization once crystals had been nucleated. In contrast, when 4-week-old cell cultures were devitalized, M was found to increase immediately, even at 2 mmol beta-GP. These results suggest that, in MC3T3-E1 cell cultures, cell viability is essential for prevention of spontaneous mineralization of the extracellular matrix.

3T3 Cells↗
PubMed1991

Biosynthesis of bone proteins [SPP-1 (secreted phosphoprotein-1, osteopontin), BSP (bone sialoprotein) and SPARC (osteonectin)] in association with mineralized-tissue formation by fetal-rat calvarial cells in culture.

To determine the relationship between the expression of bone proteins and the formation of mineralized-tissue matrix, the biosynthesis of non-collagenous bone proteins was studied in cultures of fetal-rat calvarial cells, which form mineralized nodules of bone-like tissue in the presence of beta-glycerophosphate. The temporal pattern of protein synthesis in both mineralizing and non-mineralizing cultures was studied by metabolic labelling with [35S]methionine, 35SO4(2-) or 32PO4(3-) over a 5-day period. After a 24 h labelling period, the culture media were harvested and the cell layers extracted sequentially with aq. 0.5 M-NH3, followed by 4 M-guanidinium chloride (GdmCl), 0.5 M-EDTA and a second extraction with 4 M-GdmCl. Protein associated with collagenous bone matrix was analysed after digestion with bacterial collagenase. On the basis of [35S]methionine labelling, the major proteins extracted from the mineralizing matrix were secreted phosphoprotein-1 (SPP-1; osteopontin), bone sialoprotein (BSP) and a 14 kDa phosphoprotein. The presence of SPP-1 and BSP in the conditioned media of both mineralizing and non-mineralizing cultures and their incorporation into the mineralizing nodules indicated that these proteins associate with preformed mineral crystals. However, some BSP was also present in GdmCl extracts and, together with a 35 kDa sulphated protein, was released from a bacterial-collagenase digestion of the tissue residue in both non-mineralizing and mineralizing cultures. Two forms of sulphated SPP-1 were identified, a highly phosphorylated 44 kDa species being the predominant form in the mineralized matrix. The BSP was more highly sulphated but less phosphorylated than SPP-1. Bone SPARC (secreted protein, acid and rich in cysteine) protein (osteonectin) was present almost entirely in the conditioned media and did not incorporate 32PO4(3-) or 35SO4(2-). The SPP-1 and the 14 kDa protein were susceptible to thrombin digestion, the 44 kDa SPP-1 being specifically cleaved into 28 and 26 kDa fragments. The fragments were labelled uniformly with [35S]methionine, but the 28 kDa fragment incorporated more 35SO4(2-), but less 32PO4(3-), than the 26 kDa fragment. These studies demonstrate that SPP-1 and BSP are the major osteoblast-derived bone proteins to bind to the bone mineral. That BSP also binds to the collagenous bone matrix indicates a potential role for this protein in linking the hydroxyapatite with collagen.

Animals↗
PubMed2005

Long-term effects of elemental mercury on renal function in miners of the Idrija Mercury Mine.

BACKGROUND: The kidneys are one of the main target organs for elemental mercury (Hg(0)). The influence of Hg(0) on kidneys has been extensively studied but the long-term effects on this organ have not yet been determined with certainty. The basic aim of this research was to study the effects of a long-term exposure to Hg(0) vapours on the renal function in miners in the post-exposure period. METHODS: The population studied comprised 53 miners (33 active and 20 retired) from the Idrija Mercury Mine as the exposed miners group and 53 unexposed workers as the control group. On the basis of mine exposure records (air and biological monitoring), the environmental and biological indicators of the past exposure to Hg(0) were calculated for each miner. Kidney function was determined in both groups, i.e. in the exposed miners as well as in the controls. Glomerular kidney function was evaluated by a quantitative analysis of albumin and IgG in urine. Tubular kidney function, however, was determined by a quantitative analysis of alpha(1)-microglobulin in urine and by the enzymatic activity of N-acetyl-beta-d-glucosaminidase (NAG). RESULTS: The mean exposure time in miners was 15 years. The total number of cycles of exposure ranged from 13 to 119. The mean annual time-weighted exposure was 0.29 mg m(-3) and the mean integrated exposure intensity (IEI) was 1413 mg m(-3)-h. Throughout the period of exposure the average urine mercury concentration in miners was 68.24 microg l(-1) and the average sum of peak urine mercury concentrations was 3901 microg l(-1). Albumin, IgG and alpha(1)-microglobulin in urine were significantly elevated in the exposed miners compared with the unexposed controls (t = 2.17, P = 0.03; t = 2.81, P < 0.01; and t = 2.07, P = 0.04). No significant differences were found in the urine NAG activity when the exposed miners and the unexposed workers were compared. Among the indicators of renal function only alpha(1)-microglobulin in the urine correlated significantly with the IEI (r = 0.73; P <or= 0.01) and with the sum of peak mercury urine concentrations (r = 0.67; P <or= 0.01) in the group of miners who still worked, while no significant correlations were found between these parameters in the group of the retired miners. CONCLUSION: The results of the differences in albumin, IgG and alpha(1)-microglobulin concentrations in urine between the exposed miners and unexposed controls suggest that a long-term occupational exposure to Hg(0) could cause renal dysfunction. A high correlation between alpha(1)-microglobulin in urine and the IEI as well as between alpha(1)-microglobulin in urine and the sum of peak urine mercury concentrations in the group of active but no longer exposed miners indicates that a long-term occupational exposure to Hg(0) may cause a non-permanent tubular dysfunction.

Adult↗
PubMed2005

DMP1 depletion decreases bone mineralization in vivo: an FTIR imaging analysis.

UNLABELLED: The role of DMP1 in mineralization was analyzed by comparing bone mineral and matrix properties in dmp1-null female mice to heterozygous and wildtype controls by FTIR imaging spectroscopy. The observed decreased mineral content in dmp1 null mice indicates a key role for dmp1 in bone mineralization. Indirect effects of DMP1 on other systems also determine the KO phenotype. INTRODUCTION: Dentin matrix protein 1 (DMP1), an acidic phosphorylated extracellular matrix protein, is highly expressed in mineralized tissues. In vitro, DMP1 peptides can promote or inhibit mineralization depending on the extent of phosphorylation, the peptide size, and concentration. To clarify the biological function of DMP1 protein on in vivo mineralization, this study analyzed bone properties of dmp1 knockout (KO) mice compared with heterozygous (HET) and wildtype (WT) controls. MATERIALS AND METHODS: Tibias from dmp1 KO and age-, sex-, and background-matched HET and WT mice at 4 and 16 weeks (N(total) = 60) were examined by Fourier transform infrared imaging (FTIRI), histology (n = 6 per genotype and age; N = 36), and geometry by muCT (n = 4 per genotype and age; N = 24). Serum ionic calcium and phosphate concentrations were also determined. RESULTS: The mineral-to-matrix ratios (spectroscopic parameter of relative mineral content) were significantly lower in dmp1 KO mice tibias compared with WT and HET at 4 and 16 weeks. The mineral crystallinity (crystal size/perfection) was significantly increased in dmp1 KO and HET mice relative to WT. Collagen cross-link ratios (a spectroscopic parameter related to the relative amounts of nonreducible/reducible collagen cross-links) in dmp1 KO were not significantly different from WT and HET. Based on muCT, cortical bone cross-sectional areas at 16 but not 4 weeks were significantly reduced in the KO compared with controls. Maximum, minimum, and polar cross-sectional moments of inertia were significantly lower in dmp1 KO than in HET at 16 weeks but not at 4 weeks. Histological analysis and muCT 3-D images suggested that dmp1 KO mice had osteomalacia. Dmp1 KO mice had significantly lower ionic calcium and phosphate concentrations relative to WT, whereas in the HET, values for phosphate were equivalent, and calcium values were decreased relative to WT values. CONCLUSIONS: The findings of decreased mineral-to-matrix ratio and increased crystal size in bones of dmp1 KO mice suggest that DMP1 has multiple roles (both direct and indirect) in the regulation of postnatal mineralization. We suggest that direct effects on mineral formation, crystal growth, and indirect effects on regulation of Ca x P concentrations and matrix turnover all contribute to the dominant phenotype in the dmp1 KO mouse.

Animals↗
PubMed1997

Expression of extracellular matrix proteins in human periodontal ligament cells during mineralization in vitro.

Periodontal regeneration is a complex process that requires coordinated responses from several cell types within the periodontium. It is generally accepted that the periodontal ligament (PDL) has a heterogeneous cell population, where some of the cells may be capable of differentiating into either cementoblasts or osteoblasts. Thus, it has been hypothesized that PDL cells play a role in promoting periodontal regeneration. However, definitive evidence to support this concept is lacking. Previously, we reported that PDL cells induce biomineralization as determined by Von Kossa histochemistry and transmission electron microscopy. To further determine the osteoblast-like properties of PDL cells, human PDL cells were exposed to dexamethasone (DEX) in order to promote an osteoblast phenotype, and then cell activity monitored during mineral nodule formation in vitro. For mineralization studies, cells were cultured in DMEM containing 10% FBS and a) vehicle only; b) ascorbic acid (50 micrograms/ml) and beta-glycerophosphate (10 mM); or c) ascorbic acid, beta-glycerophosphate and DEX (100 nM) for 30 days. In addition, the effects of DEX on PDL cells in non-mineralizing media were determined. Cells were stained weekly to evaluate mineral-like nodules, using the Von Kossa method. Northern blot analyses for mRNA steady state levels for several bone-associated proteins, i.e., osteopontin (OPN), bone sialoprotein (BSP), alkaline phosphatase (ALP), osteocalcin (OCN), alpha 2(1)(type 1) collagen and osteonectin (ON), were performed. DNA levels were also determined during the 30-day mineralization period. Under phase contrast microscopy, PDL cells in non-mineralizing media treated with DEX exhibited a more spindle-shaped morphology when compared with similar cells not exposed to DEX. Mineralizing conditions were required to induce mineral nodule formation. However, in this situation, mineral induction was independent of DEX; and furthermore, DEX-treated cells did not exhibit a different morphological pattern when compared with non-DEX treated cells. Mineral-like nodules were first seen at day 15, in concert with an increase followed by a decrease in expression of type I collagen and ON mRNA in both DEX-treated and non-treated cultures. Using Northern blot analysis for detection of specific proteins, we found that PDL cells did not express OPN, BSP, OCN, or ALP under any of the conditions used in this study. DEX did not alter DNA content in the cultures during the mineralization period. These results confirm that human periodontal ligament cells can be induced to mineralize in vitro and indicate that dexamethasone does not significantly alter the extent and pattern of mineralization.

Alkaline Phosphatase↗
PubMed1998

The mental and physical health of miners following the 1992 national pit closure programme: a cross sectional survey using General Health Questionnaire GHQ-12 and Short Form SF-36.

BACKGROUND: In the twelve months following the announcement of the UK pit closure programme in October 1992, 22,500 miners were made redundant. In 1994 we undertook a cross-sectional survey to determine whether the mental and physical health of men who had been employed in the Nottinghamshire mining industry differed from that of the general population. METHODS: A postal questionnaire was designed incorporating the General Health Questionnaire (GHQ-12), and six domains from SF-36. Questionnaires were sent to 1064 miners and ex-miners and 2097 other men in Nottinghamshire. Non-responders were sent two reminders. RESULTS: The final response rate was 51%. The percentage of responders with GHQ-12 scores of three or more (suggesting psychological disorder) was 46% for those still employed in the mining industry, 52% for unemployed former miners and 22% for working non-miners (odds ratios: 3.0 [95% C.I. 2.2-4.1] for current miners and 3.9 [95% C.I. 2.6-5.7] for unemployed miners compared with working non-miners). The miners and ex-miners also had lower scores (suggesting greater morbidity) for each of the SF-36 domains tested. When stratifying for age in respondents of social classes IIIM-V the scores of current miners were significantly lower than those of working non-miners (P < 0.01). CONCLUSIONS: This study suggests that when surveyed in 1994, men who had been employed in three Nottinghamshire collieries in 1992 were psychologically and physically disadvantaged compared with working non-miners. Whether these findings are a result of pit closures is uncertain. However, significant potential health needs have been demonstrated.

Adolescent↗
PubMed1996

Opposing effects on mitochondrial membrane potential by malonate and levamisole, whose effect on cell-mediated mineralization is antagonistic.

The act of chondrocyte preparation for primary, enchondral, mineralization is associated with a decline in mitochondrial respiration toward the end of the proliferative zone and the hypertrophic zone in the growth plate. Dexamethasone (Dex)-stimulated cultures of rat marrow stroma constitute a differentiation model simulating, in its energy metabolism, chondrocyte mineralization. In this model, early inhibition of succinate dehydrogenase (SDH) enriches the culture with mineralizing cells, whereas levamisole inhibits mineralization. Dex also increases mitochondrial membrane potential in stromal cells, especially on days 7-8 of stimulation. In the present study, suicide inhibition of SDH, by nitropropionic acid (NPA), in Dex-stimulated cells showed a dose-dependent increase in day 21 mineralization; the maximal effect was induced on days 2-4 of stimulation. Mineralization under 2-day-long exposure to NPA showed a similar trend to the previously studied effect of continuous exposure to malonate applied between days 3-11. Unlike malonate, the effect of NPA required its presence in the cultures for only 2 days and resulted in higher mineralization than that seen under 8 days of malonate. NPA delineated a period, days 2/4 to 7/9, in which inhibition of succinate oxidation is necessary to augment mineralization. During this period, NPA also exhibited OPC selection capacity. Early application of levamisole, under conditions previously shown to decrease day 21 mineralization, maintained mitochondrial membrane potential at the beginning of Dex stimulation but decreased or had little effect on it during days 5-10. By contrast, malonate previously found to increase day 21 mineralization decreased the membrane potential at the beginning of Dex stimulation but increased it later on day 7, or during days 5-10. These results indicate that during osteoprogenitor differentiation, before the mineralization stage, a surge in mitochondrial inner membrane potential during late matrix maturation may be a marker that heralds the extracellular matrix mineralization.

Alkaline Phosphatase↗
PubMed2004

Proton binding onto soil by nonelectrostatic models: isolation and identification of mineral contributions.

In this paper a methodological approach is proposed to validate mechanistic modeling for proton binding onto active sites of mineral and soil samples by reducing the uncertainty and arbitrariness of model schematization. This approach is based on the quantitative formulation (X-ray calibration method) of a simulating mineral mixture (SMM) accounting for the main mineral phases in the soil (quartz, goethite, hematite, muscovite, clinochlore). Mineral and organic contributions were separated by comparing titration curves of river sediment and SMM. Specific mineral contributions to the acid properties of SMM were separated by comparing titration models of SMM and single minerals. Different nonelectrostatic models were used for titrations of SMM and single minerals: two-site/three-KH models (one amphoteric plus one monoprotic site) for clay minerals and SMM; one-site/two-KH models (one amphoteric site) for goethite and hematite; and a one-site/one-KH model (one monoprotic site) for quartz. Crossed-comparisons of titration models allow for identifying and quantifying the specific contributions of the distinct edge hydroxyl groups of iron oxides, clay minerals, and quartz in the different pH ranges. In particularthe amphoteric sites of aluminosilicates mainly contribute in the acid-neutral pH range, the amphoteric sites of iron oxides take part in the neutral-basic range, and finally the monoprotic edge hydroxyl groups of quartz react in the upper basic region of pH. The good simulation of the acid-base properties of SMM (according to single mineral titration models and quantitative composition by X-ray) confirms both model schematization and SMM formulation. Speciation diagrams of the active sites of the different mineral components (aluminosilicates, iron oxides, and quartz) were obtained by implementing the database of a dedicated software with the apparent equilibrium constants regressed by titration modeling of single minerals.

Aluminum Silicates↗
PubMed1999

Augmentation of calvarial tissue using non-permeable silicone domes and bovine bone mineral. An experimental study in the rat.

The aim of the present study was to evaluate the effect of bovine bone mineral placement as an adjunct to a guided bone regeneration (GBR)-barrier in experimental bone augmentation. Some 18 Sprague-Dawley rats underwent flap surgery in which non-permeable silicone domes were placed on the calvaria. A test group of 9 animals received domes filled with cancellous deproteinized bovine bone mineral (Bio-Oss). The domes of 9 control animals were left empty. The experiment was terminated after 8 weeks of healing. Inspection after histologic preparation found no signs of any foreign body reaction to the implanted bovine bone mineral, which seemed to be well integrated with the augmented tissue. The control specimens healed uniformly with new bone inside the domes at the base of the calvaria. The tissue inside the domes of the test specimens had a completely different architecture with new bone both at the base of the calvaria and at a distance from the base, surrounded by and in close contact with non-mineralized tissue and remaining bovine bone mineral. Some ingrowth of soft connective tissue, most likely from the sagittal skull suture could be seen in most test and control specimens. Histomorphometric analysis revealed that the total amount of augmented tissue was significantly greater in the test group (x = 1.93 +/- 0.21 mm2) than in the control group (x = 0.99 +/- 0.22 mm2), P < 0.001). The control domes contained 0.73 +/- 0.28 mm2 augmented bone, while the corresponding value for the test specimens was 0.35 +/- 0.13 mm2, significantly less than the controls (P < 0.01). The test domes contained 0.83 +/- 0.15 mm2 newly-formed non-mineralized calvarial tissue, significantly more than the controls (x = 0.26 +/- 0.16 mm2), P < 0.001). Remaining particles of bovine bone mineral constituted 0.76 +/- 0.14 mm2, or 39%, of the total amount of augmented tissue in the test group. A considerable shrinkage to about 69% of the height of the initial fill of bovine bone mineral at surgery appeared in the test domes after 8 weeks of healing. The reason for this was probably more due to a denser packing of the bovine bone mineral during healing than to resorptive activity. It was concluded that implantation of bovine bone mineral combined with GBR technique significantly enhances augmentation of calvarial tissue. Early mineralization, however, seems to be retarded compared to non-filled control specimens. Further studies should be made to determine the long-term maturation of augmented tissue including resorption pattern of the bovine bone mineral.

Animals↗
PubMed1987

Considerations regarding the structure of the mammalian mineralized osteoid from viewpoint of the generalized packing model.

The relative magnitudes of mineral, organic and water contents of dense mammalian bone are calculated by a new theory based on recent findings: (1) The neutron diffraction studies of mineralized tissues with different densities demonstrated an inverse relationship between wet density and the equatorial diffraction spacing of the collagen. (2) The neutron studies showed there was very little mineral within the collagen fibrils. (3) A generalized packing model for collagen has been advanced to show how the equatorial spacing can be varied depending on tissue type, water content, and mineral content. (4) The water content of collagen fibrils when calculated from the generalized packing model matches the experimentally determined values for rat tail tendon fibers, bone matrix, and fully mineralized bone. A computational model was developed based on the generalized packing model. It provides a unifying approach to explain many features of mineralized fibrous collagenous tissues. The results are presented as estimates of the mineralized collagen fibril density, the volume fraction of collagen in bone, the density of the extrafibrillar space, the fraction of the e.f. space occupied by mineral and the ratio of mineral within collagen to total mineral content, each expressed as a function of wet bone density. A useful data base, available from previous studies, related mineral, organic and water weight fractions to wet bone density, for a density range from 1.7 g/cc for deer antler to 2.7 g/cc for porpoise petrosal. A second order polynomial was found for each weight fraction component, with bone density as the input variable, with a standard deviation less than 2% of total bone weight. This permits the bone properties to be related to a single variable, the wet bone density. It is seen that compacting the collagen fibrils as well as reducing the organic component weight fraction are two important factors determining the structure of the mineralized osteoid. It was concluded that voids and pore spaces may occupy at least 5% of the bone volume.

Animals↗
PubMed1997

Effects of proteoglycan modification on mineral formation in a differentiating chick limb-bud mesenchymal cell culture system.

In the presence of 4 mM inorganic phosphate, differentiating chick limb-bud mesenchymal cells plated in micromass cultures form a mineralized matrix resembling that of chick calcified cartilage. To test the hypothesis that cartilage proteoglycans are inhibitors of cell mediated mineralization, the synthesis, content, and turnover of proteoglycans were altered in this system, and the extent of mineralization and properties of the mineral crystals examined. In all cases where the proteoglycan synthesis or proteoglycans present were modified to provide fewer or smaller molecules, mineralization was enhanced. Specifically, when proteoglycan synthesis was blocked by treatment with 10(-10) M retinoic acid, extensive mineral deposition occurred on a matrix devoid of both proteoglycans and cartilage nodules. The crystals, which formed rapidly, were relatively large in size based on analysis by X-ray diffraction or FT-1R microspectroscopy, and were more abundant than in controls. When 2.5 or 5 mM xylosides were used to cause the synthesis of smaller proteoglycans, the extent of mineral accretion was also increased relative to controls; however, the matrix was less affected, and the extent of mineral deposition and the size of the crystals were not as markedly altered as in the case of retinoic acid. Modification of existing proteoglycans by either chondroinase ABC or hyaluronidase treatment similarly resulted in increased mineral accretion (based on 45Ca uptake or total Ca uptake) relative to cultures in which the proteoglycan content was not manipulated. Crystals were more abundant and larger than in control mineralizing cultures. In contrast, when proteoglycan degradation by metalloproteases was inhibited by metal chelation with o-phenanthroline, the Ca accretion at early time points was increased, but as mineralization progressed, Ca accumulation decreased. These data provide evidence that in this culture system, proteoglycans are inhibitors of mineralization.

Animals↗
PubMed1998

Opposing effects of cyclosporin A and tyrphostin AG-1478 indicate a role for Src protein in the cellular control of mineralization.

Cyclosporin A (CsA) induces osteoporosis but not through direct activation of osteoclasts. CsA also inhibits cell-mediated mineralization in marrow stromal cell culture, whereas the tyrphostin AG-1478 increases mineralization. These antagonistic effects on mineralization were used to discern molecules that underwent phosphorylation changes in association with their opposing effects on mineralization. In parallel, quantitative changes in Src protein were followed. Multiple dexamethasone (DEX)-stimulated stromal cell cultures were grown with and without a mineralization-inhibiting dose (0.1 microM) of CsA and were harvested on different days of DEX stimulation. Immunoblots of gel-fractionated cell extracts showed that the most noticeable changes in tyrosine phosphorylated proteins (TPP) were seen on day 8 of DEX stimulation. At least 15 TPP bands, mostly smaller than 53 kDa, were more prominent in CsA-treated cultures on day 8. Under CsA, Src protein quantity decreased on day 8, but its cleavage product (52/54 kDa) was sixfold more abundant then on day 7. Day 8 was chosen to test the effect of AG-1478 on the CsA-induced TPP changes. Dimethyl sulfoxide (DMSO) alone, the solvent of AG-1478, increased mineralization in CsA-treated versus CsA-untreated cultures and slightly decreased Src and its cleavage product. AG-1478 at 5 microM, in CsA cultures increased the specific alkaline phosphatase activity threefold, with a slight change in mineralization relative to controls grown with DMSO alone. This was accompanied by decreased intensity of several TPP bands smaller than 36 kDa. In contrast, treatment with 50 microM of AG-1478 increased the intensity of TPP bands at the same molecular size range. This high AG-1478 dose decreased cell counts selecting mineralizing cells. The results indicate that increased Src protein cleavage product on day 8 by CsA is associated with mineralization inhibition, which is opposed by DMSO and 50-microM AG-1478, thus antagonizing the effect of CsA on mineralization. Direct or indirect interaction between Src and TPP, antagonistically affected by CsA and AG-1478, is likely to underlay cellular control of mineralization. Changes in p19 and p29 intensity showed association with mineralization that was reflected by a significant direct and inverse correlation, respectively, with calcium precipitation per cell.

Animals↗
PubMed2006

Regional differences in architecture and mineralization of developing mandibular bone.

The goal of this study was to investigate the mutual relationship between architecture and mineralization during early development of the pig mandible. These factors are considered to define the balance between the requirements for bone growth on the one hand and for load bearing on the other. Architecture and mineralization were examined using micro-CT, whereas the mineral composition was assessed spectrophotometrically in groups of fetal and newborn pigs. The development of the condyle coincided with a reorganization of bone elements without an increase in bone volume fraction, but with an increase in mineralization and a change in mineral composition. In the corpus, the bone volume fraction and mineralization increased simultaneously with a restructuring of the bone elements and a change in mineral composition. The growth of the condyle was reflected by regional differences in architecture and mineralization. The anterior and inferior regions were characterized by a more dense bone structure and a higher mineralization as compared to posterior and superior regions, respectively. In the corpus, growth was mainly indicated by differences between buccal and lingual plates as well as between anterior, middle, and posterior regions characterized by a more compact structure and higher mineralization in the lingual and middle regions. In conclusion, the architecture and mineralization in the condyle and corpus started to deviate early during development toward their destiny as trabecular and cortical bone, respectively. These results were compatible with those obtained with mineral composition analysis. Regional differences within condyle and corpus reflected known developmental growth directions.

Animals↗
PubMed1995

Analysis of cell-mediated mineralization in culture of bone-derived embryonic cells with neurofibromatosis.

von Recklinghausen neurofibromatosis (NF1) is an autosomal dominant genetic disorder associated with congenital pseudoarthrosis and with short stature. To examine whether the NF1 phenotype includes functional osteogenic defects, embryonic bone-derived cells affected with NF1 were tested in culture for specific alkaline phosphatase (ALP) activity and cell-mediated mineralization and compared with other embryonic bone derived cells. NF1 showed a relatively higher specific ALP activity, which has further increased in response to dexamethasone + beta-glycerophosphate (beta GP) (Dex medium) coordinately with a decrease in cell proliferation. In In the control group, two samples showed increased ALP activity, one showed decreased activity and the forth one did not show any change in ALP. NF1 cells were distinguished from other cells regarding day 21 mineralization, they did not mineralize when cultured with ascorbate alone in the absence of Dex medium, whereas control cells did mineralize. Adding beta GP resulted in mineralization by NF1 cells but less than in other cells. In addition, NF1 cells responded to dexamethasone by increasing the beta GP-induced mineralization, as opposed to cells from other embryonic bones, which either did not respond or have even decreased mineralization under dexamethasone. Upon cis-hydroxyproline exposure, Dex medium has also distinguished NF1 cell ALP activity from that of other cell origins. Inhibition of respiratory complex II by malonate showed that most embryonic bone-derived cells of 12 weeks gestation are malonate resistant; thus, malonate selection was ineffective. This is in contrast to rat marrow stromal cells previously shown to undergo mineralizing cell enrichment in response to malonate. Exposure to levamisole, of Dex-treated cells, at days 0-11 has inhibited day 21 mineralization in all tested cultures in spite of the increase in day 11-specific ALP activity. Both malonate and levamisole did not distinguish NF1 cells from the osteogenic phenotype of other cells. Essentially embryonic bone-derived cells from 12 weeks gestation, cultured in the absence of beta GP, retained their mineralization capacity, which does not increase under dexamethasone, as distinguished from NF1 cells which require beta GP for mineralization and positively respond to dexamethasone. Therefore, bone-derived NF1 cells may be useful for studying the regulation of the mineralization process.

Alkaline Phosphatase↗
PubMed1992

Experimental changes in mineral content of juvenile mouse femora.

Juvenile laboratory mice were exposed to hypergravity (8 g), burrowing exercise, swimming to exhaustion, an anabolic steroid, and swimming and an anabolic steroid for 30 days to determine the variability of skeletal mineralization during growth. Changes in mineralization were correlated with changes in bending strength. Experimental mouse femora were loaded to failure in a cantilever beam configuration to determine bending strength, and ashed to determine total mineral content. Between experimental groups, mineral content ranged from 66.0 to 71.2% with the greatest change from the control being a 4.7% decrease in mineralization in the male swimming exercise group (P less than 0.001). Within two age-matched experiments, the first showed that the group with the greatest decrease in mineralization also had the greatest reduction in bending strength (P less than 0.001). The second age-matched experiment showed that the group with the greatest reduction in mineralization had bending strength greatly reduced (P less than 0.001). However, in this experiment, the weakest femora were in the anabolic steroid group that did not have the mineral content reduced. We conclude that (1) mineralization of juvenile mouse femora is extremely variable given varied conditions of exercise or loading; (2) mineralization of normal bone is decreased more often and to a greater extent than increased from normal exercise controls; (3) the decrease in mineralization seen here can decrease bending strength; and (4) the decrease in mineralization seen was not caused by a decrease in a mechanical loading but was probably due to a corticosterone-mediated psychological stress response.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗