Abnormal bone development: histopathology of skeletal dysplasias.
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Minireview: transcriptional regulation in development of bone.
Regulation of gene expression by transcription factors is one of the major mechanisms for controlling cellular functions. Recent advances in genetic manipulation of model animals has allowed the study of the roles of various genes and their products in physiological settings and has demonstrated the importance of specific transcription factors in bone development. Three lineages of bone cells, chondrocytes, osteoblasts, and osteoclasts, develop and differentiate according to their distinct developmental programs. These cells go through multiple differentiation stages, which are often regulated by specific transcription factors. In this minireview, we will discuss selected transcription factors that have been demonstrated to critically affect bone cell development. Further study of these molecules will lead to deeper understanding in mechanisms that govern development of bone.
Amino Acid Motifs↗
Different pattern of alkaline phosphatase, osteopontin, and osteocalcin expression in developing rat bone visualized by in situ hybridization.
Alkaline phosphatase (AP), osteopontin (OP), and osteocalcin (OC) are expressed during osteoblastic differentiation. However, previous studies suggested differences in the timing and possibly the site of their expression. In this study we used in situ hybridization to follow the distribution of these osteoblastic markers during bone development. Frozen sections of neonatal rat long bones and calvariae were hybridized with 35S-labeled RNA probes complementary to the AP, OP, and OC mRNAs. Controls included sections hybridized with the sense (mRNA) probes or pretreated with RNase. Positive cells were identified in all areas of bone formation of the long bones and calvariae. Based on quantitative silver grain distribution and density, high levels of OP expression were present only in osteoblasts in close proximity to bone (one to two cell layers). OC expression, apparently at lower levels than OP, was also localized to osteoblasts in contact with bone. In contrast AP, which was expressed at lower levels than OP, was present in a large number of cells, including preosteoblasts that were many layers removed from the bone-forming surface. These findings are consistent with the asynchronous expression of phenotypically related genes and suggest that AP is an earlier differentiation marker than OP and OC during the formation of endochondral and membranous bone.
Alkaline Phosphatase↗
The development of bone strength at the proximal radius during childhood and adolescence.
Current investigations of bone development mostly focus on bone mass, but bone strength may be functionally more important than mass. Therefore, we compared the developmental changes in cortical bone mass (BMCcort) and parameters of cortical bone strength [polar moment of inertia, section modulus, and strength strain index (SSI)]. Analyses were performed at the 65% site of the proximal radius using peripheral quantitative computed tomography. The study population comprised 469 healthy subjects, 6-40 yr of age (273 females). Both in prepubertal children (pubertal stage 1) and after puberty (pubertal stage 5 and adults) all studied parameters were significantly higher in males. During puberty (pubertal stages 2-4) the gender-specific differences were generally somewhat smaller. All of the measured parameters increased significantly with age and pubertal stage. However, although the percent increase in BMCcort between the youngest children and adults was similar between the genders, the increases in polar moment of inertia, section modulus, and SSI were higher in males. The ratio between section modulus and BMCcort was consistently higher in males after the age of 11 yr and after pubertal stage 2. Similar results were found for ratios between polar moment of inertia or SSI and BMCcort. These results show that for a given bone mass, males have stronger bones than females after pubertal stage 2. This reflects the fact that in puberty males add bone mostly on the periosteal surface, where the effect on bone strength is highest, whereas females add bone on the endocortical surface, which has a small effect on bone stability. The purpose of the mechanically inefficient endocortical apposition in female puberty might be to create a reservoir of calcium for future pregnancy and lactation.
Adolescent↗
A Xenopus DNA microarray approach to identify novel direct BMP target genes involved in early embryonic development.
Bone morphogenetic proteins (BMPs), a subgroup of the transforming growth factor-beta (TGF-beta) superfamily, were originally isolated from bone on the basis of their ability to induce ectopic bone development. Although BMPs are involved in a wide range of developmental and physiological functions, very few vertebrate target genes in this pathway have been identified. To identify target genes regulated by the BMP growth factor family in Xenopus, large-scale microarray analyses were conducted to discover genes directly activated by this factor in dissociated animal cap tissues treated with a combination of the protein synthesis inhibitor cycloheximide and BMP2. Consequent expression patterns and behaviors of the most highly induced genes were analyzed by in situ and reverse transcriptase-polymerase chain reaction analyses. Here, we describe two sets of the most highly induced direct BMP target genes identified using microarrays prepared from two different stages of early Xenopus development. A wide variety of genes are induced by BMP2, ranging from cell cycle controllers, enzymes, signal transduction cascade components, and components of the blood and vascular system. The finding reinforces the notion that BMP signals play important roles in a variety of biological processes.
Animals↗
Basic fibroblast growth factor stimulates osteoclast recruitment, development, and bone pit resorption in association with angiogenesis in vivo on the chick chorioallantoic membrane and activates isolated avian osteoclast resorption in vitro.
Increased local osteoclast (OC)-mediated bone resorption coincides with angiogenesis in normal bone development and fracture repair, as well as in pathological disorders such as tumor-associated osteolysis and inflammatory-related rheumatoid arthritis or periodontal disease. Angiogenic stimulation causes recruitment, activation, adhesion, transmigration, and differentiation of hematopoietic cells which may therefore enable greater numbers of pre-OC to emigrate from the circulation and develop into bone-resorptive OCs. A chick chorioallantoic membrane (CAM) model, involving coimplantation of a stimulus in an agarose plug directly adjacent to a bone chip was used to investigate if a potent angiogenic stimulator, basic fibroblast growth factor (bFGF), could promote OC recruitment, differentiation, and resorption in vivo. Angiogenesis elicited by bFGF on the CAM was accompanied by increased OC formation and bone pit resorption (both overall and on a per OC basis) on the bone implants in vivo. In complementary in vitro assays, bFGF did not directly stimulate avian OC development from bone marrow mononuclear cell precursors, consistent with their low mRNA expression of the four avian signaling FGF receptors (FGFR)-1, FGFR-2, FGFR-3, and FGFR-like embryonic kinase (FREK). In contrast, bFGF activated isolated avian OC bone pit resorption via mechanisms inhibited by a selective cyclo-oxygenase (COX)-2 prostaglandin inhibitor (NS-398) or p42/p44 MAPK activation inhibitor (PD98059), consistent with a relatively high expression of FGFR-1 by differentiated avian OCs. Thus, bFGF may sensitively regulate local bone resorption and remodeling through direct and indirect mechanisms that promote angiogenesis and OC recruitment, formation, differentiation, and activated bone pit resorption. The potential for bFGF to coinduce angiogenesis and OC bone remodeling may find clinical applications in reconstructive surgery, fracture repair, or the treatment of avascular necrosis. Alternatively, inhibiting such bFGF-dependent processes may aid in the treatment of inflammatory-related or metastatic bone loss.
Allantois↗
Temporal variation of c-Fos proto-oncogene expression during osteoblast differentiation and osteogenesis in developing rat bone.
To delineate the implication of c-fos protooncogenic in the osteogenie process, we have investigated the temporal pattern of c-fos mRNA expression in fetal and neonatal rat bone during intramembranous and endochondral bone formation. Northern blot analysis of mRNA extracted from calvaria and femur showed that expression of c-fos, Histone H4, and osteocalcin mRNAs followed a temporal sequence during bone development. The levels of histone H4 mRNA, a marker of cell proliferation, were high at early stages of fetal development of calvaria and femur, and decreased until birth. In both the postnatal calvaria and femur, c-fos mRNA levels increased transiently at birth and preceded a rise in osteocalcin transcripts, a marker of the mature osteoblast phenotype. The immunohistochemical analysis showed that c-Fos protein was expressed in osteoprogenitor cells in the perichondrium and periosteum, and not in mature osteoblasts which expressed markers of differentiated osteoblasts such as type-I collagen, bone sialoprotein, and osteocalcin. Thus, the transient c-fos proto-oncogene expression during the postnatal life that precedes the osteocalcin expression may be involved in the transition from the precursor state to mature osteoblasts. These results suggest that c-fos proto-oncogene may play an important role in osteogenesis during rat postnatal life.
Animals↗
Active gelatinase B is identified by histozymography in the cartilage resorption sites of developing long bones.
In order to determine which proteinases mediate the resorption of endochondral cartilage in the course of long bone development, a novel assay called "histozymography" has been developed. In this assay, frozen sections of tibial head from 21-day-old rats are placed for 4 hr at room temperature on light-exposed photographic emulsion (composed of silver grains embedded in gelatin). We report a localized but complete digestion of emulsion gelatin facing two tissue sites which are, therefore, presumed to contain an active proteinase. One of the sites is localized at the growth plate surface forming the epiphysis/metaphysis interface. The other consists of small patches located within the epiphysis at the edge of the marrow space. Both sites are engaged in the resorption of endochondral cartilage. In both sites, inhibitor tests have established that the involved proteinase is a gelatinase. Furthermore, the use of neutralizing antibodies against gelatinase A or B have demonstrated that only those that are specific for the latter block the reaction. That gelatinase B is present in the two sites has been confirmed by light microscopic immunohistochemistry. Finally, when immunoelectron microscopy is used for fine localization of the cartilage structures that form the epiphysis/metaphysis interface, the enzyme is detected within the 0.5-microm thick edge of the cartilage, and outside the cartilage, it is present in debris composed of type II collagen-rich fibrils in various states of digestion. It is concluded that gelatinase B attacks the edge of an endochondral cartilage and helps to solubilize the type II-collagen-rich fibrillar framework, which is then released as debris for further digestion. This final step opens the way to invasion by capillaries, thereby making possible the replacement of cartilage by bone. Dev Dyn 1999;215:190-205.
Animals↗
Regulating bone growth and development with bone morphogenetic proteins.
There are many gene products reported to promote osteoblast differentiation and thus increase bone formation, but only the transcription factor Runx2 and members of the bone morphogenetic protein (BMP) family of growth/differentiation factors have been shown to be absolute requirements for osteogenesis. Mice lacking the transcription factor Runx2 (also known as cbfa1) develop no bone. Similarly, osteoblast differentiation and bone formation is blocked when BMP signaling is suppressed by overexpression of noggin, a selective BMP antagonist. It is therefore not unexpected that several different mechanisms have evolved to regulate the effects of BMP-induced signaling. In this session we focus on the multiple ways in which cells can modulate BMP-induced osteogenesis and mechanisms by which BMP signaling can lead to transcriptional control of gene expression.
Animals↗
Effect of prenatal ethanol exposure on fetal calcium metabolism.
Alcohol consumption has adverse effects on both adult and developing bone. The mechanisms by which alcohol affects bone, however, are unknown. This study examined the possibility that maternal alcohol consumption may affect fetal bone development by altering fetal levels of parathyroid hormone (PTH), 1,25(OH)2D, or calcitonin (hormones that regulate calcium (Ca) and bone metabolism in the adult animal). Female Sprague-Dawley rats were bred and divided into three groups: 1 group was fed lab chow ad libitum (Control; C) and the other 2 groups received a liquid diet with (Ethanol; E) or without (Pair-fed; PF) ethanol. Blood from dams and fetuses was collected on day 21 of gestation, and selected fetuses were stained for determination of the degree of bone ossification. Mean fetal body weight and fetal skeletal ossification were reduced in the E compared with PF and C groups. Total Ca levels in fetal serum, however, showed a trend to be increased in E compared with PF and C fetuses, and no significant group differences were found in fetal serum levels of albumin, PTH, or calcitonin. Serum levels of 25-OH-D and 1,25(OH)2D were significantly decreased in E and PF, compared with C fetuses. Total Ca levels in maternal serum did not vary with the group; however, serum albumin levels were higher in E, compared with PF and C dams, suggesting that serum ionic Ca levels may have been reduced in the E dams. Serum levels of 25-OH-D were reduced in the E, compared with PF and C dams, whereas levels of 1,25(OH)2D were elevated. PTH levels did not vary among groups. Interestingly, serum calcitonin levels were elevated in the E, compared with PF and C, dams. These results indicate that the effects of ethanol on fetal bone development do not appear to be related to alterations in fetal serum levels of PTH, 1,25(OH)2D, or calcitonin. Maternal ethanol consumption, however, results in reduced appetite and a decrease in dietary Ca intake. Despite the reduced Ca intake, the ability of the dam to maintain Ca homeostasis appeared intact, although this may be dependent on the duration of ethanol consumption.
Alcohol Drinking↗
Utilization of microgravity bioreactors for differentiation of mammalian skeletal tissue.
Bioreactor cell and tissue culture vessels can be used to study bone development in a simulated microgravity environment. These vessels will also provide an advantageous, low maintenance culture system on space station Freedom. Although many types of cells and tissues can potentially utilize this system, our particular interest is in developing bone tissue. We have characterized an organ culture system utilizing embryonic mouse pre-metatarsal mesenchyme, documenting morphogenesis and differentiation as cartilage rods are formed, with subsequent terminal chondrocyte differentiation to hypertrophied cells. Further development to form bone tissue is achieved by supplementation of the culture medium. Research using pre-metatarsal tissue, combined with the bioreactor culture hardware, could give insight into the advantages and/or disadvantages of conditions experienced in microgravity. Studies such as these have the potential to enhance understanding of bone development and adult bone physiology, and may help define the processes of bone demineralization experienced in space and in pathological conditions here on earth.
Animals↗
Role of CSF-1 in bone and bone marrow development.
There is a close interaction between the processes involved in osteogenesis and hemopoiesis. In developing bone, the osteoclasts, cells of hemopoietic origin, resorb and invade the calcified cartilage rudiment. As a result, the primitive marrow cavity is formed and hemopoiesis initiates. Osteogenic cells-osteoblasts and osteocytes-control the development and activity of the osteoclasts through the local release of factors. One factor responsible for this osteoblast-osteoclast interaction is colony-stimulating factor-1 (CSF-1). Studies performed on the osteopetrotic op/op mouse mutant have established that this factor is essential for proliferation and differentiation of the osteoclasts. Expression of CSF-1 receptors by mature osteoclasts and osteoclast precursors strongly suggests that CSF-1 action is exerted directly on cells of this lineage. In vivo, CSF-1 synthesis by osteoblasts is temporally and spatially related to sites of osteoclast development. Thus CSF-1 may represent one of the factors responsible for coupling hemopoiesis to osteogenesis. In vitro, osteoblasts express at least 4 transcripts encoding either a secreted or a membrane-bound form of CSF-1. At the protein level, osteoblasts in vitro synthesize the membrane-bound form and secrete the majority of CSF-1 as a proteoglycan, a small fraction of which is integrated into the matrix. These different molecular forms may locally restrict the biological action of this cytokine. Indeed, injection of recombinant human CSF-1 in op/ op mutants does not correct the osteoclast deficiency in the metaphyseal spongiosa of long bones, and sclerosis persists at this site. Similarly, the deficiency of some tissue macrophage populations in op/op mice is only partially or not at all corrected by injection of CSF-1. The expression of CSF-1 receptors by mature osteoclasts may imply that CSF-1 also influences their bone resorbing activity. Indeed, CSF-1 has been shown to induce osteoclast fusion, spreading, and survival. These findings suggest that CSF-1 is essential for the proliferation, differentiation, activity, and survival of tissue macrophages and osteoclasts, cells involved in tissue turnover. Furthermore, they corroborate the view that both osteoclasts and tissue macrophages stem from a CSF-1-dependent common precursor along the macrophage lineage.
Animals↗
A theoretical model of endochondral ossification and bone architectural construction in long bone ontogeny.
The role of mechanical stresses in the formation of endochondral ossification patterns and the construction of basic bone architecture in human long bones is investigated using a three-dimensional generalized model of long bone development. The distribution of mechanical stress which is created in developing bones as a result of intermittent mechanical loading is calculated using a computer model that mathematically represents the bone's geometry, material properties and loading conditions. The process of endochondral ossification is simulated by iteratively converting cartilaginous regions of the computer model to bone, based on the calculated intermittent hydrostatic and shear stress distributions. Once local regions of mineralized bone have formed, these regions are remodeled according to an algorithm which relates bone density to a mechanical stress stimulus. The results simulated the correct sequence of the appearance of morphological structures which are common to long bones in the human appendicular skeleton. These developmental structures include the site of the first endochondral bone and the secondary ossification center and the tubular nature of long bones. Our results suggest that mechanical loading histories may influence bone morphogenesis beginning from the early stages of endochondral ossification and continuing throughout life. The stress-based algorithms may be part of the 'rules of construction' or 'developmental constraints' which guide limb ontogeny.
Algorithms↗
Alterations in bone turnover and impaired development of bone mineral density in newly diagnosed children with cancer: a 1-year prospective study.
In the present study, longitudinal changes in bone mineral density, bone turnover, and bone hormonal metabolism were evaluated in newly diagnosed children with cancer. Lumbar spine (L2-L4) and femoral neck bone mineral densities (grams per cm2) were measured by dual energy x-ray absorptiometry in 28 children (age, 2.9-16.0 yr; median, 8.0 yr; 10 acute lymphoblastic leukemias, 18 solid tumors) at diagnosis and after a 1-yr follow-up. Apparent volumetric density (grams per cm3) was calculated to minimize the effect of bone size on BMD. Serum levels of osteocalcin (OC), type I collagen carboxyl-terminal propeptide (PICP), and type I collagen carboxyl-terminal telopeptide were measured serially during the study. Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, insulin-like growth factor I (IGF-I), and IGF-binding protein-3 were analyzed at diagnosis and at 1-yr follow-up. A significant decrease in femoral bone mineral density and apparent volumetric density was observed during the year after diagnosis [(mean (SD), -10.1% (8.8%) and -11.3% (8.1%) respectively; P < 0.01], whereas age- and sex-matched controls showed annual increments of +5.4% (7.7%; P < 0.01) and +0.7% (5.7%; P = NS) respectively. The markers of bone formation (PICP and OC) were significantly decreased at diagnosis. By the end of the follow-up, PICP and OC were normalized, whereas the marker of bone resorption (type I collagen carboxyl-terminal telopeptide) was significantly increased. Reduced levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and IGF-binding protein-3 were observed during the study. To conclude, increased bone resorption and impaired development of femoral bone density were observed in children with cancer during chemotherapy. Deficient accumulation of bone mass may lead to impaired development of peak bone mass and predispose children with cancer to increased risk of osteoporosis and diminished skeletal resistance to fractures later in life.
Absorptiometry, Photon↗
Platelet-derived growth factor (PDGF)-AA: a self-imposed cytokine in the proliferation of human fetal osteoblasts.
PDGF, a multiple mitogen, stimulates osteoblast replication and bone collagen degradation, and it has been described as a key factor in bone metabolism. Recently, PDGF was disclosed to be the autocrine cytokine of human osteoblasts. PDGF's effect on human bone development needs elucidation, and the mechanism of PDGF-AA autocrining remains unclear. In this work, osteoblasts were isolated from human fetal calvaria which resemble the cells in developing bone tissue. Using an in vitro model, the effect of PDGF-AA on the cells was investigated with the results showing that (i) after PDGF-AA was added into the medium for 24 h, PCI of the cells increased by 48.2% (P<0.05), and PCI decreased after the removal of PDGF-AA. (ii) 24 h after treatment with PDGF-AA, the percentage of osteoblasts in G(0)/G(1)phase decreased and that in S phase increased. (iii) The expression of PDGF-A mRNA was upregulated by PDGF-AA, PDGF-BB, TGFbeta,and bFGF respectively. These results proved that: (i) PDGF-AA enhances cell replication by accelerating cell recycle and inducing the quiescent cells into the proliferation portion of cell cycle. (ii) PDGF-AA is a self-imposed cytokine in human fetal osteoblast replication.
Bone Development↗
Computer model of endochondral growth and ossification in long bones: biological and mechanobiological influences.
Endochondral growth and ossification, the processes by which cartilage increases in size and is replaced by bone, are affected by biological factors such as intrinsic genetic makeup and systemic chemical agents. In addition, these processes are affected by epigenetic mechanical factors: they may be accelerated in regions of intermittent high shear stress and decelerated in regions of intermittent high hydrostatic pressure. Previous models of bone development have not incorporated both biological and mechanobiological influences on endochondral growth and ossification. We have implemented a finite element analysis to model a developing bone rudiment from 8 weeks of gestational development to approximately 2 years after birth. As a function of time, we calculated a maturity index that reflects the progression of a region of cartilage through the endochondral ossification sequence of proliferation, hypertrophy, mineralization, and replacement by bone. We calculated a specific growth rate for each region of cartilage and estimated overall longitudinal growth of the rudiment. Regions of cartilage replaced by bone were remodeled. The results from the maturity index can be compared with distributions of proliferative, hypertrophic, and mineralized cartilage seen on histology at various stages in development. The results of the simulation predicted prenatal and postnatal developmental events, including formation of a secondary ossific nucleus, a layer of articular cartilage, and a growth plate. Our results demonstrate the necessity to include biological and mechanobiological influences when endochondral growth and ossification are considered.
Animals↗
Role of microenvironmental deterioration of the bone marrow in the development of bone atrophy in magnesium silicate-treated rats.
The role of microenvironmental deterioration of the bone marrow in the development of bone atrophy was examined in rats with bone atrophy induced by magnesium silicate. In the tibial metaphyses, proliferation of myelocytic elements of haematopoietic tissue was prominent and caused narrowing of sinusoids, increased distance between sinusoids and trabecular bone and atrophy of trabecular bone. There was a significant correlation in volume percentage between haematopoietic cells and trabecular bone, between haematopoietic cells and sinusoids and between sinusoids and trabecular bone. These results imply that atrophy of trabecular bone is related to microenvironmental deterioration of the bone marrow, that is, a decrease in efficiency of exchange of nutrients and waste products between sinusoids and trabecular bone due to the proliferation of haematopoietic cells and a deficiency of nutrient supply to the bone marrow due to the narrowing of sinusoids.
Animals↗
Muscle mass during childhood--relationship to skeletal development.
Bone densitometric data often are difficult to interpret in children and adolescents because of large inter- and intraindividual variations in bone size. Here, we propose a functional approach to bone densitometry that addresses two questions: Is bone strength normally adapted to the largest physiological loads, that is, muscle force? Is muscle force adequate for body size? To implement this approach, forearm muscle cross-sectional area (CSA) and bone mineral content (BMC) of the radial diaphysis were measured in 349 healthy subjects from 6 to 19 years of age (183 girls), using peripheral quantitative computed tomography (pQCT). This functional approach to pediatric bone densitometric data should be adaptable to a variety of densitometric techniques.
Absorptiometry, Photon↗