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PubMed1992

Recurrence of lethal osteogenesis imperfecta due to parental mosaicism for a mutation in the COL1A2 gene of type I collagen. The mosaic parent exhibits phenotypic features of a mild form of the disease.

We have determined that a man, ascertained because he fathered a child with lethal osteogenesis imperfecta (OI) with each of two partners, is mosaic in both his germline and somatic tissues for a mutation in the COL1A2 gene which encodes the pro alpha 2(I) chain of type I procollagen. His dermal fibroblasts were previously shown to synthesize a population of cysteine-containing alpha 2(I) chains that were posttranslationally overmodified. DNA sequence analysis of COL1A2 cDNAs demonstrated that the cysteine-containing chain resulted from a point mutation (G to T) in the first position of the codon for the glycine at residue 472 of the triple helical domain. Genomic DNA from the one available affected infant contained the mutant and normal COL1A2 alleles in equal proportion. Examination of DNA from several tissues of the father showed that the mutant allele was present in approximately 40% of his sperm, 80% of his lymphocytes, and nearly 100% of his dermal fibroblasts. Despite the high level of mosaicism detected in somatic tissues, the only phenotypic manifestation of OI in the proband was that he was shorter than his unaffected male relatives and had mild dentinogenesis imperfecta. Thermal stability of type I collagen molecules containing the substitution was decreased, but to a lesser extent than for a nonlethal cysteine for glycine substitution at residue 259 of alpha 2(I), indicating that this measure of molecular stability may be of limited use in explaining the pathogenesis of osteogenesis imperfecta.

Adult↗
PubMed2004

Effect of the difference of bone turnover on peri-titanium implant osteogenesis in ovariectomized rats.

High and low bone turnover situations, both of which are typically observed as postmenopausal and senile osteoporosis, were created by ovariectomy (OVX), and then an investigation of whether or not the difference of bone turnover affected peri-titanium (Ti) implant osteogenesis in rats was conducted. Female rats were divided into four groups. The experimental and control groups underwent OVX or sham operations at 15 or 27 weeks of age, as high or low bone turnover groups, respectively. Ti implants were inserted into the tibiae at 30 weeks, then fluorochromes were injected 10 or 20 days after the implantation for histometry. The implants were retained for 30 days and then ground sections were prepared. Afterward, the cortical bone growth rate, bone contact ratio (BCR) of the implant in both the cortical bone area and medullary canal area, and the average trabecular bone thickness around the implant were evaluated. Biochemical markers of bone turnover were also measured. Biochemical measurements indicated both increasing osteocalcin production in OVX rats and decreasing tartrate-resistant acid phosphatase activity in the low-turnover group. Histometrical measurements showed decreasing cortical growth and low BCR in the medullary canal of the low-turnover group. The high-turnover group demonstrated BCR as high as that of the control group. There was no significant difference in the average trabecular bone thickness around the implant among the groups. As a result, two types of osteoporotic situations were confirmed and it was shown that the difference of bone turnover was clearly due to the diverse osteogenesis around the Ti implant.

Acid Phosphatase↗
PubMed2005

Solution-mediated effect of bioactive glass in poly (lactic-co-glycolic acid)-bioactive glass composites on osteogenesis of marrow stromal cells.

A previous study demonstrated that the incorporation of bioactive glass (BG) into poly (lactic-co-glycolic acid) (PLGA) can promote the osteoblastic differentiation of marrow stromal cells (MSCs) on PLGA by promoting the formation of a calcium-phosphate-rich layer on its surface. To further understand the mechanisms underlying the osteogenic effect of PLGA-BG composite scaffolds, whether solution-mediated factors derived from composite scaffolds/hybrids can promote osteogenesis of marrow stromal cells was tested. The dissolution product from PLGA-30%BG scaffold stimulated osteogenesis of MSCs, as was confirmed by increased mRNA expression of osteoblastic markers such as osteocalcin (OCN), alkaline phosphatase (ALP), and bone sialoprotein (BSP). The three-dimensional structure of the scaffolds may contribute to the production of cell-derived factors that promoted distant MSC differentiation. Thus PLGA-BG composites demonstrate significant potential as a bone-replacement material.

Adult↗
PubMed1992

Expression of mutant alpha (I)-procollagen in osteoblast and fibroblast cultures from a proband with osteogenesis imperfecta type IV.

This study compares the synthesis of mutant type I collagen in cultured dermal fibroblasts and trabecular osteoblasts that were isolated from a patient with moderately severe osteogenesis imperfecta (type IV). Previous study of this patient's dermal fibroblasts revealed a 2000 dalton deletion located in cyanogen bromide peptide 4 of alpha 2(I)-collagen. The phenotype of the bone cell cultures was defined by a 3-4 day logarithmic phase doubling time, predominantly type I collagen production over type III and alkaline phosphatase activity 13.5 times dermal fibroblast levels. The current study revealed that both fibroblasts and osteoblasts synthesized a normal and a shortened alpha 2(I) chain, each as the product of separate alleles. Following pepsin treatment of the procollagens, a shortened alpha 1(I) chain was also seen in both cell types. Cyanogen bromide peptide mapping of osteoblast alpha-chains demonstrated the same deletions in the cyanogen bromide peptide 4 as observed in the fibroblast cyanogen bromide maps. PAGE analysis of oligonucleotide-specific cDNA that was reverse transcribed from RNA isolated from fibroblasts and osteoblasts also demonstrated the presence of two bands, one the normal size of alpha 2(I) cDNA and a second species that was smaller by 54 base pairs. Sequencing of polymerase chain reaction-amplified cDNA fragments revealed an in-frame deletion of exon 12. This finding was confirmed by the RNase protection method. Genomic DNA sequencing detected a T----G point mutation in the second position of the 5' splice donor site of intron 12. Therefore, in this patient with osteogenesis imperfecta there was no qualitative alteration in the osteoblast-specific expression of this mutant alpha 2(I)-collagen allele compared to dermal fibroblasts.

Alkaline Phosphatase↗
PubMed1995

Bone fragility in transgenic mice expressing a mutated gene for type I procollagen (COL1A1) parallels the age-dependent phenotype of human osteogenesis imperfecta.

An inbred strain of transgenic mice that expressed a mutated gene for type I procollagen and that developed spontaneous fractures was used to study the effects of age on the phenotype of fragile bones. The mutated gene has been shown to cause depletion of type I collagen in the transgenic mice because it generated shortened pro alpha 1(I) chains that bound to and produced degradation of normal pro alpha 1(I) chains synthesized from the endogenous mouse COL1A1 gene. For this study, femurs from transgenic mice ranging in age from 0.5-24 months were examined. The results demonstrated that the level of expression of the transgene was independent of age. Femurs from the transgenic mice were more fragile than controls at 0.5 and 1.5 months, they were biomechanically normal at 6 months, and then they were more fragile at 24 months. The normal biomechanical properties of the bones from the transgenic mice at 6 months were accompanied by periosteal thickening of the bones together with an increase in the collagen content that was not associated with a proportional increase in mineral content. The results indicated that the effects of age, mechanical stress, and hormonal action produced a biological compensation for the mutated gene by either increasing collagen synthesis of bone, decreasing collagen degradation, or both. The biological compensation was apparently lost by 24 months when the outer diameters of the femurs were again less than in controls, the cortical thickness was about the same as in controls, and both the collagen and mineral contents were less than controls. The results demonstrated that bone fragility in the transgenic mice paralleled the age-dependent phenotype of human osteogenesis imperfecta. Therefore the transgenic mice appeared to be useful models for osteogenesis imperfecta. They also may be useful models for some forms of osteoporosis.

Aging↗
PubMed1996

Limited chondro-osteogenesis by recombinant human transforming growth factor-beta 1 in calvarial defects of adult baboons (Papio ursinus).

The therapeutic utility of a single application of recombinant human transforming growth factor-beta (hTGF-beta) has not been previously tested in large osseous wounds in primates. Sixteen calvarial defects, 25 mm in diameter, were prepared in four adult male baboons (Papio ursinus). In each animal, three defects were treated with increasing doses of hTGF-beta 1 in conjunction with baboon insoluble collagenous bone matrix as carrier (5, 30, and 100 micrograms of hTGF-beta 1/g of matrix). The fourth defect was implanted with collagenous matrix without hTGF-beta 1 as control. Serial undecalcified sections were prepared from the specimens harvested on day 30. Islands of cartilage and endochondral osteogenesis were found in hTGF-beta 1-treated defects, irrespective of the doses used. Histomorphometry of the defect site showed no significant differences between control and hTGF-beta 1-treated specimens with regard to bone and osteoid volumes. However, analysis of the regenerated tissue in proximity to the defect margins only showed that, on average, greater amounts of bone formed in specimens that were treated with 5 and 30 micrograms of hTGF-beta 1 when compared with controls. This suggests a possible effect on osteoblastic cells originating from the periosteal and endosteal spaces of the severed calvaria. Overall, however, this difference has no therapeutic implications for the healing of large cranial wounds in primates. The present findings indicate that a single application of hTGF-beta 1, in conjunction with collagenous matrix, results in limited chondro-osteogenesis in defects of membranous bone of adult baboons.

Analysis of Variance↗
PubMed2002

Estrogen-induced osteogenesis in mice is associated with the appearance of Cbfa1-expressing bone marrow cells.

Cbfa1 is a transcription factor recognised as being involved in early osteoblast differentiation during embryonic skeletogenesis. To determine whether Cbfa1 plays a similar role in bone formation in the adult, we analysed whether its expression is altered during estrogen-induced osteogenesis, following our recent studies which suggest that this response involves the generation of early osteoblast precursors within bone marrow. To facilitate identification of Cbfa1-expressing cells, these studies were performed in mice heterozygous for a cbfa1 gene deletion (cbfa1(+/-)) using beta-galactosidase (lacZ) as a genetic marker. Cbfa1-expressing cells were identified by lacZ staining of longitudinal sections of the proximal tibial metaphysis. Treatment of cbfa1(+/-) mice with 17beta-estradiol 0.5 mg/week for 24 days led to the appearance of new cancellous bone surfaces. This response was associated with a marked increase in number of Cbfa1-expressing cells within the metaphysis, consisting not only of osteoblasts on bone surfaces but also of cells within the adjacent bone marrow. We subsequently enumerated Cbfa1-expressing cells at earlier time-points following estrogen, in sections co-stained for ALP activity. After 4 days of estrogen treatment, a population of cells appeared within the marrow cavity which expressed Cbfa1, but were negative for ALP. At later time-points, large numbers of Cbfa1 + bone marrow cells were still present, but the majority of these were close to new trabecular bone surfaces at sites which showed high levels of ALP activity. An equivalent distribution of Cbfa1-expressing cells was observed in further studies where Cbfa1 expression was analysed in wild-type mice by immunohistochemistry. We conclude that estrogen-induced osteogenesis is associated with the appearance of a population of Cbfa1-expressing cells within bone marrow, which we hypothesize to represent the osteoblast precursor population responsible for subsequent new bone formation.

Animals↗
PubMed2002

Developmental morphology of limb reduction in Hemiergis (Squamata: Scincidae): chondrogenesis, osteogenesis, and heterochrony.

Digit loss is a common theme in tetrapod evolution that may involve changes in several developmental processes. The skink genus Hemiergis provides an ideal model to study these processes in closely related taxa: within three Western Australian Hemiergis species, digit quantity ranges between two and five. For three consecutive reproductive seasons, gravid females of Hemiergis were collected in the field and their embryos prepared for histological analysis of limb skeletal development (chondrogenesis and osteogenesis). Comparative studies of skeletal developmental morphology demonstrate that limbs with fewer than five digits do not result from a simple truncation of a putative ancestral (five-digit) developmental program. The developmental and adult morphologies in two-, three-, and four-digit Hemiergis are neither predicted nor explained by a simple model of heterochrony involving either chondrogenesis or osteogenesis. In postnatal Hemiergis, digit number and relative limb length do not correlate in a simple linear fashion. Instead, limb size and digit reduction may correlate with substrate conditions and burrowing behavior.

Animals↗
PubMed1979

The timing of the onset of osteogenesis in the tibia of the embryonic chick.

Haematoxylin, Alcian Blue-Chlorantine Fast Red (ABCR) and the Ralis osteoid-specific stain were employed to closely follow the histogenesis of the tibia of the embryonic chick so as to provide an accurate description of the onset of ossification. An overview of the major cytological events preceding osteogenesis in the tibia was obtained from hindlimbs of embryos of H. H. (Hamburger and Hambilton, '51) stages 16-26 (2.5-5 days of incubation) stained with ABCR. A description of the cytological changes in the periosteum as it develops from the perichondrium and an analysis of the timing of the onset of osteoid deposition was obtained from the tibiae of accurately aged and staged embryos of H. H. stages 28-32 (5.5-8 days). These tibiae were stained specifically for the detection of osteoid: the freshly-secreted, unmineralized product of fully-differentiated osteoblasts. The perichondrium transformed into a bi-layered periosteum at H. H. late stage 29 (6.5 days) while osteoid was first detected adjacent to the hypertrophic cartilage of H. H. stage 30 (6.5-7 days) tibial diaphyses. These results, correlated with the immunoflourescent studies of Von der Mark et al. ('76a,b), which revealed the presence of Type I (bone-type) collagen-synthesizing cells in the perichondria of tibiae from embryos of H. H. stage 28 (5.5-6 days), demonstrated that the onset of determination of cells for osteogenesis and the cytodifferentiation of the periosteum are not temporally coupled.

Animals↗
PubMed1985

Medullary osteogenesis with platinum cathodes.

Studies of electrical stimulation of osteogenesis with stainless steel electrodes have previously established a dose-response relationship between current and bone growth. Examination of the effect of differing geometric current densities resulted in the conclusion that very little electrode surface area was involved in stimulation and led to the design of a multiport "distributive" cathode. A series of experiments were performed to extend these results to wire and multiport platinum electrodes. As before, a current-bone growth dose-response relationship was found. Peak bone growth was greater than for stainless steel. However, peak bone growth occurred at 2.0 microA (versus 20 microA for stainless steel). Correlation studies suggest that small changes in cathodic potential affect bone growth more than similar size changes in current. Finally, the generally benign local host response to platinum suggests that platinum may be a suitable material for chronic indwelling anodes for stimulation of osteogenesis.

Animals↗
PubMed1995

Effect of bone cylinder length on distraction osteogenesis in the rabbit tibia.

The viability and osteogenic potential of bone cylinders for bone transport was investigated in one tibia of 18 mature male New Zealand rabbits. The length of the bone cylinder was equal to or twice that of the diameter of the tibia. The cylinder was cut subperiosteally with an externally cooled oscillating saw from a lateral approach, after a specific unilateral external fixator had been applied. To simulate bone transport, one end of the cylinder was fixed to the distal bone stump by a cerclage wire and healing and revascularization was prevented by an interposed expanded polytetrafluoroethylene membrane. The periosteum was re-adapted and sutured, and distraction began 10 days postoperatively at 0.25 mm/12 hours for 22 days. New bone formation in the distraction gap was quantified by dual energy x-ray absorptiometry and by computer-assisted histomorphometry of polyfluorochrome-labeled undecalcified bone sections and corresponding microradiographs. In half of the animals with each size cylinder, osseous bridging occurred, so the findings on distraction osteogenesis are reported only for the remaining nine animals. Generally, centripetal mineralization of the gap with two distinct zones of ripening bone structures and a central radiolucent fibrocartilaginous zone could be distinguished. Neither absorptiometry nor histomorphometry showed significant differences in the overall amount of this new bone formation for the bone cylinders of two different lengths. However, osteogenesis was significantly greater at the proximal end than at the cylinder. New bone was formed predominantly from endosteal sites in the smaller cylinders and from periosteal sites in the larger cylinders. Histologically, there was complete necrosis of both sizes of cylinders, followed by revitalization through newly formed vascular channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1999

Effect of lengthening rate on angiogenesis during distraction osteogenesis.

This study investigated the angiogenic response to four varying rates (0.3, 0.7, 1.3, and 2.7 mm/day) of distraction in a rabbit model of leg-lengthening. Immunostaining was performed with use of specific antibodies to type-IV collagen and endothelial cell antigen to examine semiquantitatively the presence of blood vessels in the developing tissues. With use of the Chalkley counting method, the greatest number of positive-staining blood vessel cells was found in the central fibrous zone of the groups that underwent lengthening at 0.7 and 1.3 mm/day compared with any other zone in any group (p < 0.05, t test). There were no statistical differences in the positive labeling indices in the mineralization front and the new bone zone adjacent to the mineralization front in any of the groups. However, the decrease in the number of positive-staining blood vessel cells in the new bone zone distant to the mineralization front compared with any other zone in any group was statistically significant. The results suggest that during distraction osteogenesis, the precursor cells of new capillaries were present in abundance within the fibrous interzone. These cells connected into the capillary network at the junction of the mineralization front and the fibrous zone. The angiogenic response was weaker in the more mature regions within the new bone zones. A slow rate of distraction (0.3 mm/day) did not maximally stimulate angiogenesis in the central fibrous zone, whereas high rates (2.7 mm/day) appeared to impair this response. In this model of distraction osteogenesis, the vascularization process in the central fibrous zone was maximally stimulated at distraction rates of 0.7 and 1.3 mm/day.

Animals↗
PubMed2000

Primary resective shortening followed by distraction osteogenesis for limb reconstruction: a comparison with simple lengthening.

Resective distraction osteogenesis is a new approach to treat segmental diaphyseal bone defects by primary limb shortening and secondary distraction osteogenesis from the same site. A rabbit model was introduced to compare the bone-regeneration characteristics of this technique with those of simple lengthening procedures. Twenty-four skeletally mature New Zealand White rabbits were divided into two equal groups. In the test group, limbs were lengthened after a 10-mm segmental diaphyseal bone resection and limb shortening. In the control group, a simple subperiosteal osteotomy for limb lengthening was performed without resection. New bone formation was evaluated mechanically, radiologically, histomorphometrically, and densitometrically. Bone bridging occurred in all animals. Normalized mechanical values for the newly reconstructed tibiae demonstrated similar torsional stiffness (71+/-3.3 compared with 71+/-8.2%; p = 0.95) and strength (64+/-5.3 compared with 68+/-7.3%; p = 0.66) in the two groups. The average normalized callus diameter was significantly greater in the test group than in the control group (p < 0.01). The remodeling index calculated from densitometry, however, showed a significantly less progressed stage of remodeling in the test group (p < 0.05). Histomorphometric analysis of the callus center supported this finding, showing significantly lower values for trabecular thickness (p < 0.05) and total bone volume (p < 0.01) in the test group. The results demonstrated the possibility of new bone formation after resection and monofocal shortening. This suggests a new therapeutic option to treat diaphyseal segmental bone defects.

Absorptiometry, Photon↗
PubMed2000

Quantitative assessment of in vivo bone regeneration consolidation in distraction osteogenesis.

We present a new method for quantitatively assessing the consolidation of bone regeneration by performing distraction osteogenesis in micropigs. We measured in vivo stiffness using a newly developed, revolving, bone-healing meter. After the micropigs were killed, we obtained maximum torsional moment data for the regenerated bones by destructive mechanical testing, and we then correlated these data with the data for stiffness. We found a highly significant regression between in vivo stiffness and maximum torsional moment (r2 = 0.80), suggesting that monitoring stiffness may be useful for the prediction of bone regeneration in distraction osteogenesis. Therefore, our method may be a reliable tool for future quantitative monitoring of healing progress in patients with healing bones or in animal studies addressing treatments to increase bone formation in long-bone defects.

Animals↗
PubMed2006

Low intensity pulsed ultrasound accelerated bone remodeling during consolidation stage of distraction osteogenesis.

Bone regeneration in distraction osteogenesis occurs under tensile stress with axial rhythmic distraction after osteotomy. In this study, we evaluated if the low intensity pulsed ultrasound (LIPUS) was also effective on enhancement of bone remodeling during consolidation stage of distraction osteogenesis. Open osteotomy of seventeen 18-week-old female New Zealand rabbit tibiae were performed. The distraction was applied with the rate of 1 mm per day. LIPUS (30 mW/cm(2), 1.5 MHz) was delivered for 20 min per day during 4-week consolidation stage (n=10). The animals without treatment served as sham group (n=7). Plain X-ray, peripheral quantitative computational tomography (pQCT), and torsional test were performed. Results showed that smaller radiolucent interzone of LIPUS treatment group was gradually occupied by calcified tissue in plain X-ray at week 2. The bone mineral density (BMD) measured on radiographs increased by 9.18% in the LIPUS group. Bone mineral content (BMC), hard callus volume, and bone strength index (BSI) measured by pQCT were 83%, 116%, and 94%, respectively, in LIPUS group that were significantly greater than those of the controls. At the 4th week, LIPUS-treated callus showed the development of neocorticalization in the proximal and distal region. The BMC, hard callus volume, and BSI of LIPUS group decreased and was not significantly different from control. This was also confirmed by the maximum torque of LIPUS-treated callus (1424.2+/-457.3 N . mm) obtained at week 4, which did not differ from that of the sham group (1968.8+/-895.1 N . mm). In conclusion, the effective period of LIPUS treatment was at the initial stage of consolidation, with accelerated bone formation and remodeling.

Animals↗
PubMed2006

Radiographic classification of osteogenesis during bone distraction.

Successful limb lengthening requires serial radiological evaluation of the progression of healing of the regenerate bone. However, there is no radiographic classification system that shows how the regenerate should progress during treatment in adults. The study aimed to address this need.A series of radiographs were studied from 92 patients (125 segments) who had undergone bone lengthening. A radiographic classification of osteogenesis was developed based on callus shape and radiographic features that occur between osteotomy and fixator removal. This classification system used both shape and type of feature to condense and record the radiographic information, but type of feature alone was sufficient to predict outcome. The concurrence and reproducibility of the classification system was tested by inter- and intra-observer studies. The degree of consistent repetition and agreement between observers suggests that the classification system is reliable, reproducible, and therefore should be robust in use. This classification system provides an insight into osteogenesis; it allows the progress of the bone healing to be assessed against a successful pattern of healing. Hence, potential problems can be predicted and clinical changes made to improve outcome. The classification can be simplified to make it more appropriate for clinical use.

Adolescent↗
PubMed2006

Dose-dependent effect of low-intensity pulsed ultrasound on callus formation during rapid distraction osteogenesis.

Distraction osteogenesis of bone or callotasis causes poor bone formation when the distraction rate is beyond the optimal rate. Low-intensity pulsed ultrasound was reported to enhance fracture healing, treatment of nonunion, and accelerate bone maturation and remodeling during consolidation stage of distraction osteogenesis. In this study, we evaluated the efficacy of different durations of LIPUS treatments during rapid bone lengthening. After 7-day latent period, osteotomized New Zealand white rabbit tibiae were lengthened at the rate of 2 mm per day for 1 week. Two different LIPUS treatment durations of 20 min and 40 min were selected for treatment groups. Rabbits without treatment served as the control group. Plain X-ray, peripheral quantitative computed tomography (pQCT) and histology were performed to assess bone acquisition in the distraction callus. The results showed that LIPUS increased bone mineral content and volume of the mineralized tissue of distraction callus in a dose-dependent manner. The different regions of distraction callus exhibited various spatial response to LIPUS treatment. Moreover, LIPUS enhanced dose-dependant endochondral formation. Compared with 20-min treatment, the 40-min LIPUS treatment was a more favorable treatment duration for bone regeneration in the distraction callus. In conclusion, LIPUS was able to enhance bone regeneration under rapid distraction, and its effect was dose-dependent.

Animals↗
PubMed1991

Prenatal diagnosis of severe osteogenesis imperfecta.

The ultrasound findings in a series of 15 prenatally diagnosed cases of severe osteogenesis imperfecta types IIA, IIB, IIC, and III are described, eleven being detected on routine scans of women with no relevant history. As most cases of osteogenesis imperfecta type IIA are dominant sporadic mutations, the importance of prenatal diagnosis during routine scanning at a local level is emphasized. In addition to characteristic broad, shortened and fractured long bones, striking features of the chest and head are highlighted which may be encountered during a routine scan, prompting further assessment.

Female↗