Effects of vitamin D on developing bones and teeth.
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Bone Development↗
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Matrix protein profiles in calf bone development.
The major noncollagenous proteins (NCP) of the mineralized extracellular matrix of bovine bone were present from early fetal life through adulthood. The alpha 2-HS-glycoprotein was the dominant bone NCP at 2 months in utero and then diminished with advancing fetal age. Osteocalcin levels were quite low in early fetal bone, became elevated near term, reached a maximum shortly after birth, and dropped again in adult bone. Osteonectin levels were relatively constant at all stages of bone development, but somewhat lower values were seen in woven bone than in lamellar bone matrix. For a given fetus, NCP profiles were identical in both flat and long bones. The 24,000 dalton phosphoprotein was significantly elevated in fetal secondary spongiosa, bony areas known to be undergoing extensive resorption. Adult bone matrix contained greater quantities of lower and intermediate molecular weight NCPs compared to actively forming fetal bone.
Animals↗
Bone development.
The sequential cellular and molecular details of the initial embryonic formation of bone can be used to gain insight into the control of this process and subsequent bone physiology and repair. The functioning of osteogenic cells is governed by a complex balance between the intrinsic capacities of these cells in the context of extrinsic information and signalling. As with other mesenchymal tissues, the balance of intrinsic versus extrinsic capacities and influences is central to understanding both the sequence and consequence of bone development. It has been suggested that the cartilaginous model which forms at the centre of limbs is responsible for, and provides the scaffolding for, subsequent bone formation. Our recent studies of the embryonic chick tibia indicate that osteogenic progenitor cells are observed before the formation of the chondrogenic core. In particular, a layer of four to six cells, referred to as Stacked Cells, forms around a prechondrogenic core of undifferentiated cells. These osteoprogenitor cells give rise to all of the newly forming bone. Importantly, this newly forming bone arises outside and away from the chondrogenic core in a manner similar to the intramembranous bone formation seen in calvariae. Indeed, the cartilaginous core is replaced not by bone but by vascular and marrow tissues. The interplay between the osteogenic collar and the chondrogenic core provides an environment which stimulates the further differentiation of the cartilage core into hypertrophic cartilage and eventually renders this core replaceable by vascular and marrow tissue. There is an intimate relationship between the osteogenic cells and the vasculature which is obligatory for active bone formation. Bone formation in long bones, such as the tibia, as well as in the calvaria seems to proceed in a similar manner, with vascular tissue interaction being the most important aspect of successful osteogenesis, as opposed to the presence or interaction of cartilage. Our studies have focused on the development of long bones in aves, but detailed study of mouse and man indicates that many of the general features observed for birds apply to bone development in mammals. It is our current thesis that the general rules governing embryonic formation of long bones also apply to the formation of ectopic bone and are related to aspects of fracture repair.
Animals↗
Follistatin and activin in bone: expression and localization during endochondral bone development.
The involvement of activin and follistatin, an activin-binding protein, in endochondral bone development was examined by sc implantation of demineralized bone matrix in rats. Immunoreactive follistatin was localized in proliferating chondrocytes and round osteoblasts, whereas it was not detected in hypertrophic chondrocytes and osteoblasts surrounding bone marrow. Western blot analysis also revealed that immunoreactive follistatin was higher during the initial stages of chondrogenesis (day 5) and osteogenesis (days 11 and 14) and lower during the conversion from cartilage to bone (day 9). These results suggest that follistatin is produced by proliferating cells, and the expression decreases with differentiation of the cells. Implants injected with follistatin on days 9 and 10 contained lower calcium levels on day 14 than those injected with rat albumin. Furthermore, the follistatin-injected implants were still mainly composed of cartilage, suggesting that the disappearance of follistatin is necessary for the conversion of cartilage to bone. In contrast, immunoreactive activin beta A (55-60 kDa) was continuously detected in implants on days 7-14. The content of C propeptide of type II procollagen was increased and cartilageous area was enlarged on day 7 by activin A injections on days 5 and 6, suggesting a chondrogenic effect of activin in the initial stage of cartilage formation. These results indicate that proliferating chondrocytes and round osteoblasts produce follistatin, and that the activity of activin is regulated by changes in the expression of follistatin at the stages of chondrogenesis and transition from cartilage to bone.
Activins↗
The role of BMP-6, IL-6, and BMP-4 in mesenchymal stem cell-dependent bone development: effects on osteoblastic differentiation induced by parathyroid hormone and vitamin D(3).
Human bone marrow-derived mesenchymal stem cells (MSCs) represent an ideal source for cell therapy for inherited and degenerative diseases, bone and cartilage repair, and as target for gene therapy. The role of the combination of human parathyroid hormone (PTH) and vitamin D(3) in bone formation and mineralization has been established in several osteoblast cell culture studies. The aim of the present study was to evaluate the role of this hormonal combination alone and in the presence of bone morphogenetic protein-4 (BMP-4) or-6 (BMP-6) in inducing osteogenic differentiation of human MSC. Human MSC derived from adult normal bone marrow that are positive for CD29, CD44, CD105, and CD166 and negative for CD14, CD34, and CD45, were treated with the PTH and 1,25-dihydroxyvitamin D(3) in the presence and absence of recombinant human BMP-4 or BMP6. PTH and vitamin D(3) induced high levels of expression of two key markers of bone formation: osteocalcin and alkaline phosphatase by MSCs. BMP-6 but not BMP-4 increased osteocalcin expression induced by PTH and vitamin D(3). Both BMPs enhanced calcium formation in MSC cultures and this response was potentiated by PTH and vitamin D(3). The present results revealed a novel potent effect of PTH and vitamin D(3) plus BMPs in inducing bone development by human MSCs. These results may facilitate therapeutic utility of MSCs for bone disease and help clarify mechanisms involved in stem cell-mediated bone development.
Adult↗
Multiple cellular phenotypes in an insertional mutation in mouse affecting bone development.
The 6093 line of transgenic mice exhibits altered bone development as a result of an insertional mutation by the transgene. Female transgenic mice show a marked kyphosis as early as 2 weeks of age. Vertebrae from female mice have lower total bone area and mineral content than age-matched, gender-matched controls, although the bone mineral density is not changed. The femur and tibia exhibit the opposite effect-increased bone area and mineral content. Fluorescent bone label experiments indicated an increased rate of bone mineral deposition in the femur during the early postnatal growth period, and bone marrow from femurs of 6093 females had increased numbers of fibroblast colony-forming units. Transgenic females also are obese and have altered thymocyte development, suggesting that the insertional mutation affects multiple cell populations. We hypothesize that these phenotypes arise as a result of an alteration in the function or developmental potential of a stromal cell or mesenchymal stem cell.
Animals↗
Influence of aluminum on mineralization during matrix-induced bone development.
A model of de novo mineralization employing matrix-induced endochondral bone formation in rats was used to study the short-term effects of aluminum on the deposition of calcium and phosphate in vivo. In experiments where systemic aluminum concentrations were elevated, the cellular processes associated with bone development appeared to be normal, if somewhat delayed, however precipitation of the mineral phase was prevented. This suggests a primary direct physical chemical effect of aluminum in vivo on calcification, as suggested by in vitro studies which demonstrate that aluminum is a potent inhibitor of calcium phosphate precipitation. Aluminum salts implanted locally with the matrix appeared to be toxic to the cellular processes leading to chondrogenesis and osteogenesis.
Alkaline Phosphatase↗
Total body bone development during early childhood in very low birth weight infants without cerebral palsy and mental retardation.
Total body bone mineral density was measured by dual energy X-ray absorptiometry in 52 children who were very low birth weight (VLBW) infants without cerebral palsy and mental retardation (postconceptional age, from 10 mo to 6 y and 6 mo). VLBW infants in this study seemed to show compensatory acceleration of total body bone development, catching up with the control group during early childhood. However, in VLBW infants with at least one of the three factors such as total parenteral nutrition for 1 week or more, assisted ventilation for 1 week or more, or oxygen therapy for 28 d or more in their early stage after birth, adequate mineral supplementation might be especially important for long-term bone development.
Aging↗
Matrix constituents of early developing bone examined by freeze fracture.
Specimens of aldehyde-fixed and glycerol-impregnated early developing bone matrix, obtained from rat calvaria, were examined by the freeze-fracture method. The developing bone matrix reveals collagen fibrils, numerous membranous structures and a granular background. The collagen fibrils, when viewed longitudinally, exhibit a substructure of thinner filaments (microfibrils) which appear to follow a twisted course along the fibril-axis. Some of the membranous structures are readily identified as osteoblast processes. Others, which are round, ovoid or irregular in shape, were found either with or without intramembrane particles (IMPs). It is concluded that the round or ovoid IMP-containing membranous structures correspond to matrix-vesicles. The nature of the IMP-free bodies, however, is uncertain. They may be artefacts or genuine matrix-vesicles deriving from unstable membrane domains which have a propensity for blebbing or budding off. Confirmation of the latter possibility might come from examination of directly frozen specimens.
Animals↗
Dietary phosphorus and food allowance of dwarf breeders affect reproductive performance of hens and bone development of their progeny.
1. An experiment was conducted with 144 caged hens to study the effects of different dietary concentrations of phosphorus and of food restriction on the reproductive performance of dwarf breeder hens and on the growth and the bone development of their progeny. 2. Severe food restrictions at 105 g/hen day compared to 115 g/hen day, decreased hen body weight and hen day egg production. Fertility was unaffected and hatchability slightly depressed by the more severe restriction. 3. Egg and one-day-old chick weights were decreased by limiting the food intake of the breeders but the negative effect disappeared at slaughter (7 weeks). 4. Shell quality decreased as the dietary phosphorus increased and was not affected by food allowance. Albumen quality was slightly impaired in severely restricted hens. 5. Serum inorganic phosphorus in hens and yolk phosphorus increased with increasing dietary phosphorus. Tibial breaking strength and tibial percentage ash of the progeny at hatching was markedly improved in proportion to maternal phosphorus and food intake. This improvement in bone quality was not maintained at 7 weeks. 6. The number of chicks affected by twisted legs (valgus) and dyschondroplasia were similar whatever the maternal diet. The frequency of valgus was higher in males than in females. 7. It is concluded that maternal food intake and phosphorus supply are of importance for the initial bone development of the progeny.
Animal Feed↗
Gene expression during endochondral bone development: evidence for coordinate expression of transforming growth factor beta 1 and collagen type I.
Subcutaneous implantation of demineralized bone particles (DBP) into rats induces the formation of a bone ossicle by a tightly controlled sequence of chondro- and osteo-inductive events which are directly comparable to those which occur in normal endochondral bone development. Although the morphological and biochemical sequence associated with endochondral bone formation in this model has been well characterized, to date little information is available as to the gene regulation by which these events occur. To examine the expression of genes in this system, RNA was isolated from implants every 2 days over a time course spanning 3 to 19 days after implantation of DBP into rats. Cellular levels of mRNA transcripts of cell-growth-regulated and tissue-specific genes were examined by slot blot analysis and compared to the morphological changes occurring during formation of the ossicle. Analysis of the mRNA levels of histone H4 and c-myc, markers of proliferative activity, revealed several periods of actively proliferating cells, corresponding to 1) production of fibroprogenitor cells (day 3), 2) onset of bone formation (day 9), and 3) formation of bone marrow (day 19). The mRNA levels of collagen type II, a phenotypic marker of cartilage, peaked between days 7 and 9 post-implantation, corresponding to the appearance of chondrocytes in the implant, and rapidly declined on day 11 (to 5% of maximum value) when bone formation was observed. The peak mRNA levels of collagen type I, found in fibroblasts and osteoblasts, occurred first with the onset of bone formation (days 7-10) and again during formation of bone marrow (day 19). This study has demonstrated that the temporal patterns of mRNA expression of cartilage type II and bone type I collagens coincide with the morphological sequence in this model of endochondral bone formation. Further, the mRNA levels of transforming growth factor beta 1 (TGF beta) were compared to those of collagen types I and II; a direct temporal correlation of TGF beta mRNA levels with that of collagen type I was found throughout the developmental time course. This observation of a tightly coupled relationship between TGF beta and type I collagen mRNA levels is consistent with a functional role for TGF beta in extracellular matrix production during in vivo bone formation.
Animals↗
The CREB family of activators is required for endochondral bone development.
We have evaluated the importance of the CREB family of transcriptional activators for endochondral bone formation by expressing a potent dominant negative CREB inhibitor (A-CREB) in growth plate chondrocytes of transgenic mice. A-CREB transgenic mice exhibited short-limbed dwarfism and died minutes after birth, apparently due to respiratory failure from a diminished rib cage circumference. Consistent with the robust Ser133 phosphorylation and, hence, activation of CREB in chondrocytes within the proliferative zone of wild-type cartilage during development, chondrocytes in A-CREB mutant cartilage exhibited a profound decrease in proliferative index and a delay in hypertrophy. Correspondingly, the expression of certain signaling molecules in cartilage, most notably the Indian hedgehog (Ihh) receptor patched (Ptch), was lower in A-CREB expressing versus wild-type chondrocytes. CREB appears to promote Ptch expression in proliferating chondrocytes via an Ihh-independent pathway; phospho-CREB levels were comparable in cartilage from Ihh(-/-) and wild-type mice. These results demonstrate the presence of a distinct signaling pathway in developing bone that potentiates Ihh signaling and regulates chondrocyte proliferation, at least in part, via the CREB family of activators.
Animals↗
Growth factors influencing bone development.
We have approached the study of growth factors affecting cartilage and bone development by investigating those factors present in bone which are able to initiate new cartilage and bone formation in vivo. This has led to the identification and molecular cloning of seven novel human factors which we have named BMP-1 through BMP-7. Six of these molecules are related to each other, and are also distantly related to TGF-beta. The presence of one of these molecules, recombinant human BMP-2 (rhBMP-2) is sufficient to produce the complex developmental system of cartilage and bone formation when implanted subcutaneously in a rat assay system. In this model, administration of rhBMP-2 ultimately results in the formation of a piece of trabecular bone, which is filled with mature bone marrow. While our studies demonstrate that rhBMP-2 by itself has the ability to induce cartilage and bone formation in vivo, we find other BMP molecules present along with BMP-2 in our highly purified nonrecombinant bone-inductive material. These results suggest that the bone inductive capacity of bone-derived proteins may reside in the combinatorial or synergistic activities of this set of BMP-2 related molecules.
Animals↗
The Indian hedgehog--PTHrP system in bone development.
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Animals↗
Accuracy of microCT in the quantitative determination of the degree and distribution of mineralization in developing bone.
PURPOSE: To evaluate the accuracy and applicability of a commercially available microCT system for comparative measurements of the degree and distribution of mineralization of developing bone. MATERIAL AND METHODS: Homogeneous K2HPO4 solutions with different concentrations (range 0-800 mg/cm3) were used to assess the accuracy of a microCT system equipped with a polychromatic X-ray source. Both high (45 kV) and low (70 kV) tube peak voltages were explored. The resulting attenuation was compared with calculated theoretical attenuation values to estimate the accuracy. As an example of its applicability, the method was used to assess changes in the degree of mineralization of various regions of the mandible from two pigs of different developmental age. RESULTS: On average, the estimated error of the measured linear attenuation was 10% or less. Accuracy was dependent on the average mineral concentration, the size of the sample, and the energy of the X-ray beam. The accuracy of the microCT system appeared sufficient to distinguish regional differences in the degree of mineralization within and between specimens of developing mandibular bone. Furthermore, the resolution of the system allowed identification of different degrees of mineralization within trabeculae. CONCLUSION: Accuracy of microCT with polychromatic radiation can be considered adequate for assessment of the degree of mineralization of developing bone. Therefore, this method provides a three-dimensional means by which to simultaneously investigate the bone structure as well as the degree of mineralization during development in a non-destructive manner and with high resolution.
Animals↗
Gene polymorphisms, bone mineral density and bone mineral content in young children: the Iowa Bone Development Study.
We examined the association of candidate gene polymorphisms with bone mineral density (BMD) and bone mineral content (BMC) in a cohort of 428 healthy non-Hispanic white children participating in the Iowa Bone Development Study, a longitudinal study of determinants of bone accrual in childhood. BMD and BMC measurements of the hip, spine and whole body were made using a Hologic 2000 Plus densitometer in 228 girls and 200 boys ages 4.5-6.5 years. Genotypes at 14 loci representing eight candidate genes [type I collagen genes (COL1A1 and COL1A2), osteocalcin, osteonectin, osteopontin, vitamin D receptor (VDR), estrogen receptor (ER), androgen receptor (AR)] were determined. Gender-specific and gender-combined prediction models for bone measures that included age, weight, height (and gender) were developed using multiple linear regression analysis. COL1A2 and osteocalcin genotypes were identified as having the strongest and most consistent association with BMD/BMC measures. Osteonectin, osteopontin and VDR translation initiation site polymorphisms were associated with some individual bone measures, but none of the associations was as consistent as those identified for the COL1A2 and osteocalcin genes. No association was identified with COL1A1 (RsaI and Sp1), VDR (BsmI) and ER polymorphisms (PvuII, XbaI, TA) and BMD/BMC. However, we identified significant gene-by-gene interaction effects involving the ER and both VDR and osteocalcin, which were associated with BMD/BMC. Our data suggest that genetic variation at multiple genetic loci is important in bone accrual in children. Moreover, the combination of genotypes as several loci may be as important as a single genotype for determining BMD and BMC.
Anthropometry↗
Expression of Stra13 during mouse endochondral bone development.
We have examined the expression of the basic helix-loop-helix factor Stra13 (DEC1/Sharp2) during endochondral bone development in the mouse. Stra13 expression was examined by in situ hybridization in the tibia from E14.5-E18.5, and at post-natal day 24. At E14.5, expression of Stra13 mRNA was very low, with expression limited to scattered hypertrophic chondrocytes. At E15.5 Stra13 mRNA was present in post-mitotic hypertrophic chondrocytes, co-localizing with collagen X expression. At E16.5-E18.5, Stra13 was expressed in both the proliferating chondrocytes and in the late hypertrophic chondrocytes. At E15.5-E18.5, Stra13 expression was also observed in the primary spongiosa. Stra13 expression was also maintained in the 24-day post-natal tibia, with expression detectable only in the late hypertrophic chondrocytes. Because Stra13 has been shown to be induced by hypoxia, and the growth plate is hypoxic during embryonic development, we compared the expression pattern of Stra13 and the HIF1-alpha target gene VEGF. VEGF is expressed predominantly in the late hypertrophic chondrocytes, with lower expression in the proliferating chondrocytes. Thus, there was a large degree of overlap in the expression patterns of Stra13 and VEGF in chondrocytes during embryonic development.
Animals↗
Co-dependence of calcium and phosphorus for growth and bone development under conditions of varying deficiency.
The purpose of this study was to quantify the effect of variation in calcium intake, with and without supplemental phosphorus, on growth and bone development in growing animals under conditions of varying calcium and phosphorus deficiency. Nine groups of weanling male rats were fed a diet nutritionally complete, except for calcium and phosphorus, for 28 days. This diet provided nine levels of varying calcium and phosphorus repletion, using either calcium carbonate, dicalcium phosphate, or tricalcium phosphate. Body weights and diet consumption were measured throughout the test period. At term, the femurs from each animal were weighed, measured for tensile strength, bone mineral content (BMC), and bone density, and analyzed for ash, calcium, phosphorus, and histology. As expected, at equivalent levels of calcium supplementation, the two phosphorus-containing salts promoted significantly greater improvement in all the bone variables measured, as well as greater body weight gain and diet and calcium utilization, compared to animals supplemented with calcium only. Histomorphometric analysis confirmed the results of the mineral analysis and showed the structural impact of the inadequate mineral intake. The mean values for ash weight, BMC, and tensile strength in the nine diet groups were well fit (R(2) values ranging from 0.93 to 0.99) by multivariate models incorporating only the diet content values for calcium and phosphorus. In these models, the value for the phosphorus coefficient was three to sixfold larger than that for the calcium term, indicating a substantially greater effect of varying phosphorus intake than of varying calcium. These results demonstrate both the co-dependence of calcium and phosphorus in bone development and the importance of providing both minerals to support soft tissue and bone growth.
Animals↗