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PubMed1996

Procollagen alpha 1(I) transcripts in cells near the interface of coralline implants in rats, detected by in situ hybridization.

Cells procollagen alpha 1(I) transcripts were demonstrated at the interface of natural coral mineral implanted in the femur of rats after 7, 14, 21 and 28 days by in situ hybridization with digoxigenin-labelled RNA probes. Procollagen alpha 1(I) transcripts were detectable in osteoblasts between 7 and 28 days after implantation. As early as 7 days after implantation, procollagen alpha 1(I) RNA expression was also demonstrated in fibroblasts; the transcripts steady state levels decreased until the 28th day, when they subsided completely. The development of bone was significantly during the 4 weeks of implantation. Inhibition of bone development by the coralline material could not be recorded.

Animals↗

PubMed2003

Characterization of osteocalcin (BGP) and matrix Gla protein (MGP) fish specific antibodies: validation for immunodetection studies in lower vertebrates.

In fish species the basic mechanisms of bone development and bone remodeling are not fully understood. The classification of bone tissue in teleosts as cellular or acellular and the presence of transitional states between bone and cartilage and the finding of different types of cartilage in teleosts not previously recognized in higher vertebrates emphasizes the need for a study on the accumulation of the Gla-containing proteins MGP and BGP at the cellular level. In the present study, polyclonal antibodies developed against BGP and MGP from A. regius (a local marine teleost fish) and against MGP from G. galeus (a Pacific Ocean shark), were tested by Western blot for their specificity against BGP and MGP from several other species of teleost fish and shark. For this purpose we extracted and purified both proteins from various marine and freshwater teleosts, identified them by N-terminal amino acid sequence analysis and confirmed the presence of gamma-carboxylation in the proteins with the use of a stain specific for Gla residues. Each antibody recognized either BGP or MGP with no cross-reaction between proteins detected. All purified fish BGPs and MGPs tested were shown to be specifically recognized, thus validating the use of these antibodies for further studies.

Amino Acid Sequence↗

PubMed2005

Timing of pulsed electromagnetic field stimulation does not affect the promotion of bone cell development.

Pulsed electromagnetic field (PEMF) devices have been used clinically to promote the healing of surgically resistant fractures in vivo. However, there is a sparsity of data on how the timing of an applied PEMF effects the osteogenic cells that would be present within the fracture gap. The purpose of this study was to examine the response of osteoblast-like cells to a PEMF stimulus, mimicking that of a clinically available device, using four protocols for the timing of the stimulus. The PEMF signal consisted of a 5 ms pulse burst (containing 20 pulses) repeated at 15 Hz. Cultures of a human osteosarcoma cell line, SaOS-2, were exposed to the four timing protocols, each conducted over 3 days. Protocol one stimulated the cells for 8 h each day, protocol two stimulated the cells for 24 h on the first day, protocol three stimulated the cells for 24 h on the second day, and protocol four stimulated the cells for 24 h on the third day. Cells were seeded with either 25,000 or 50,000 cells/well (24-well cell culture plates). All assays showed reduced proliferation and increased differentiation (alkaline phosphatase activity) in the PEMF stimulated cultures compared with the control cultures, except for protocol four alkaline phosphatase measurements. No clear trend was observed between the four protocols; however this may be due to cell density. The results indicated that an osteoblast-like cell line is responsive to a 15 Hz PEMF stimulus, which will stimulate the cell line to into an increasing state of maturity.

Bone Development↗

PubMed1994

Dual role of osteoblastic proenkephalin derived peptides in skeletal tissues.

Proenkephalin encode a group of small peptides with opiate-like activity, the endogenous opioids, known to function as neurohormones, neuromodulators, and neurotransmitters. Recently, we have demonstrated that in addition to its abundance in fetal brain tissue, proenkephalin is highly expressed in nondifferentiated mesodermal cells of developing fetuses. We identified the skeletal tissues, bone, and cartilage as major sites of proenkephalin expression. To examine the possibility that proenkephalin is involved in bone development we have studied the expression of this gene in bone-derived cells, its modulation by bone active hormones, and the effects of enkephalin-derived peptides on osteoblastic phenotype. Our studies revealed that osteoblastic cells synthesize high levels of proenkephalin mRNA which are translated, and the derived peptides are secreted. Reciprocal interrelationships between osteoblast maturation and proenkephalin expression were established. These results together with our observations demonstrating inhibitory effects of proenkephalin-derived peptides on osteoblastic alkaline phosphatase activity, strongly support the notion that proenkephalin is involved in bone development. A different direction of research by other investigators has established the capability of the opioid system in the periphery to participate in the control of pain. On the basis of these two lines of observation, we would like to present the following hypothesis: The potential of embryonic skeletal tissue to synthesize proenkephalin-derived peptides is retained in the adult in small defined undifferentiated cell populations. This potential is realized in certain situations requiring rapid growth, such as remodeling or fracture repair. We suggest that in these processes, similarly to the situation in the embryo, the undifferentiated dividing cells produce the endogenous opioids. In the adult these peptides may have a dual function, namely participating in the control of tissue regeneration and in the control of pain.

Amino Acid Sequence↗

PubMed1993

Development of bone mass and bone density of the spine and femoral neck--a prospective study of 65 children and adolescents.

The bone mineral density (BMD, g/cm2) of the lumbar spine (L2-L4) and femoral neck was measured twice with a 1-year interval by dual energy X-ray absorptiometry (DEXA) in 65 healthy children and adolescents aged 7-20 years. In addition, the BMD values were corrected for the size of bones to obtain the bone volumetric density (BMDvol, g/cm3) using a method developed previously. The annual increases of BMD and BMDvol in both spine and femoral neck were most marked in females at the time of menarche (during the age of 11-13 years), and in males between the ages of 13 and 17 years. The males showed significantly higher values in their mean annual increment rates of femoral bone mineral content (BMC) and femoral neck width, whereas no differences in spinal parameters were found. The acquisition of bone mass and bone density stopped or markedly diminished before the age of 20 years, supporting the theory that the major portion of the peak bone mass is attained in late adolescence. We could not find any significant relationship between the increment rate of bone density, and physical activity or calcium intake. This study emphasizes the significant effect of puberty and genetic factors on the development of bone mass and density.

Absorptiometry, Photon↗

PubMed2006

Direct interactions of Runx2 and canonical Wnt signaling induce FGF18.

Canonical Wnt signaling is clearly required for skeletal development and bone formation. However, the targets of Wnt signaling that convert this signal into bone are unclear. Identification of these targets will yield insight into normal bone physiology and suggest new therapeutics for treatment of bone disease. Here we show that an essential regulator of bone development, FGF18, is a direct target of canonical Wnt signaling. A single DNA binding site for the Wnt-dependent transcription factors TCF/Lef accounted for the stimulation of the fgf18 promoter in response to Wnt signaling. Additionally, targeted disruption of betacat blocked fgf18 expression in vivo. Partially overlapping the TCF/Lef binding site is a Runx2 binding site and experiments showed that Runx2 and TCF/Lef work cooperatively to induce fgf18 expression. RNA interference knockdown of Runx2 inhibited and Runx2 forced expression augmented the induction of fgf18 by canonical Wnt signaling. Significantly, Runx2 formed a complex with Lef1 or TCF4 and this complex bound the composite binding site in the fgf18 promoter. These results demonstrate that two transcription pathways that are essential for bone, physically and functionally converge at the fgf18 promoter.

3T3 Cells↗

PubMed1998

Mice lacking osteopontin show normal development and bone structure but display altered osteoclast formation in vitro.

We have used homologous recombination in embryonic stem cells to generate mice with a targeted disruption of the osteopontin (Opn, or Spp1, for secreted phosphoprotein 1) gene. Mice homozygous for this disruption fail to express osteopontin (OPN) as assessed at both the mRNA and protein level, although an N-terminal fragment of OPN is detectable at extremely low levels in the bones of -/- animals. The Opn -/- mice are fertile, their litter size is normal, and they develop normally. The bones and teeth of animals not expressing OPN are morphologically normal at the level of light and electron microscopy, and the skeletal structure of young animals is normal as assessed by radiography. Ultrastructurally, proteinaceous structures normally rich in OPN, such as cement lines, persist in the bones of the Opn-/- animals. Osteoclastogenesis was assessed in vitro in cocultures with a feeder layer of calvarial osteoblast cells from wild-type mice. Spleen cells from Opn-/- mice cells formed osteoclasts 3- to 13-fold more frequently than did control Opn+/+ cells, while the extent of osteoclast development from Opn -/- bone marrow cells was about 2- to 4-fold more than from the corresponding wild-type cells. Osteoclast development occurred when Opn-/- spleen cells were differentiated in the presence of Opn-/-osteoblasts, indicating that endogenous OPN is not required for this process. These results suggest that OPN is not essential for normal mouse development and osteogenesis, but can modulate osteoclast differentiation.

Animals↗

PubMed2005

Cleidocranial dysplasia: molecular genetic analysis and phenotypic-based description of a Middle European patient group.

Cleidocranial dysplasia (CCD) (OMIM 119600) is a rare dysplasia of osseous and dental tissue. Characteristic features are typical facial and dental appearance plus morphologic anomalies. RUNX2 (OMIM 600211), the responsible gene for CCD, is considered to be a master gene for bone development and bone homeostasis. This study describes the genotype-phenotype correlation based on craniofacial features involving an interdisciplinary approach. Our patient cohort consisted of 31 CCD patients from 20 families; five patients from two families were unavailable for clinical examination. Since CCD mostly affects the craniofacial region, phenotypic characterization of each individual focused on craniofacial and dental aspects. After recording patient medical and family history, the phenotypic data was analyzed using homogeneity analysis (HOMALS), a statistical procedure for data reduction in categorical data analysis. The coding sequence of the RUNX2 gene was analyzed using PCR, direct sequencing, and restriction endonuclease digestion. Eight unpublished and four known heterozygous mutations in a total of 14/20 index patients (70%) were identified. In total, we detected 7 missense mutations, 5 frameshift mutations, and 2 nonsense mutations in 14 index patients (35%, 25%, 10%, respectively). The overall CCD phenotype varied from mild to fullblown expression. Using HOMALS, we were able to discriminate four groups of patients showing significant differences in phenotypic expressivity, thereby simplifying the grouping of our large patient cohort into clear distinguishable entities. Analysis of the mutation patterns revealed that mutational frequency and types of mutations found can be attributed to the gene's structure and function.

Cleidocranial Dysplasia↗

PubMed1993

Different members of the fibroblast growth factor receptor family are specific to distinct cell types in the developing chicken embryo.

Single-stranded RNA probes for the three chicken fibroblast growth factor (FGF) receptors, cek-1, cek-2, and cek-3, in conjunction with in situ hybridization were used to characterize the distribution of the corresponding mRNAs in the developing chicken embryo. Cek-1 was expressed diffusely in most tissues examined, whereas the expression of cek-2 and cek-3 was more restricted. The highest levels of FGF receptor expression were seen in the developing bones; in skeletal, cardiac, and smooth muscle; and in some areas of the brain. Although all three receptors were expressed in a number of the same tissues, the expression of each receptor within a given tissue was generally specific for different cell types. In addition, the distribution of each of these receptors did not correlate with the previously characterized distributions of individual FGFs. These results suggest that the members of the FGF receptor family may represent cell-type-specific receptors rather than ligand-specific receptors. Thus, the interaction between a growth factor of the FGF family and a given FGF receptor is likely to be controlled to a large extent by spatial constraints, rather than exclusively by high binding affinities.

Animals↗

PubMed1993

Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis.

The actions of fibroblast growth factors (FGFs) are mediated via a family of four closely related FGF receptor genes (FGFRs 1-4). FGFR1, FGFR2, and FGFR4 have unique patterns of expression during embryogenesis suggesting that these receptors mediate different functions of FGFs during development. In the present study, we used in situ hybridization analysis to show that FGFR3 also has a unique pattern of expression during organogenesis. Like FGFR1 and FGFR2, FGFR3 was expressed in the germinal epithelium of the neural tube (9.5-16.5 days pc). However, at 1 day postpartum and in the adult brain, FGFR3 was expressed diffusely and localized in cells with morphologic characteristics of glia, a pattern distinctly different from the discrete neuronal expression of FGFR1. FGFR3 was also expressed at high levels in differentiating hair cells of the cochlear duct, but was not detected in other sensory epithelia. Outside the nervous system, the highest level of FGFR3 expression was found in the cartilage rudiments of developing bone. During endochondral ossification, FGFR3 was expressed exclusively in resting cartilage, a pattern distinct from FGFR1 and FGFR2 which are also expressed during this process. Unlike FGFR1 and FGFR2, FGFR3 was not detected in most other epithelial or mesenchymal tissues during these stages of organogenesis. The unique expression pattern of FGFR3 compared with the other FGF receptors strongly suggests that FGFR3 performs specific functions during organogenesis.

Animals↗

PubMed1994

rDlx, a novel distal-less-like homeoprotein is expressed in developing cartilages and discrete neuronal tissues.

From a rat chondrosarcoma we isolated a cDNA that encodes a novel homeoprotein rDlx. The homeodomain of rDlx shows a high degree of sequence identity with those of Drosophila Distal-less, mouse Dlx, and Xenopus Xdll proteins. Northern hybridization of rDlx revealed a 1.4- to 1.6-kb RNA species in a rat chondrosarcoma and a cell line derived from this tumor and in mouse C3H10T1/2 cells, but no rDlx RNA was detected in mouse NIH3T3 fibroblasts, rat skin fibroblasts, mouse C2 myoblasts, mouse myeloma S194 cells, human B-cell lymphoma Daudi cells, or human acute myelocytic leukemia cells. RNase protection assays showed that rDlx transcripts were present at high levels in 14-day-old rat embryos, 18-day-old rat embryo skeletal tissues, and adult rat brain. rDlx RNAs were present at lower levels in newborn rat rib cartilage, 18-day-old rat embryo soft tissues, newborn rat skin, and adult rat heart. rDlx transcripts were not detected in adult rat liver, spleen, lung, kidney, testis, or skeletal muscle. In situ hybridization of rat embryos at different stages revealed that rDlx transcripts were present in otic vesicle, branchial arches, apical ectodermal ridge of limb bud, developing cartilages, perichondria of mature cartilages, mesenchymal cells of developing membranous bones, developing teeth, ganglionic eminence of the telencephalon, diencephalon, olfactory epithelia, and epidermis of the skin. rDlx RNAs were also detected in the developing parasympathetic mesenteric ganglia of the gastrointestinal tract. Hence, rDlx RNAs are mainly expressed in several neuronal tissues and developing skeletal tissues.

Amino Acid Sequence↗

PubMed2004

Reconstruction surgery for patients with musculoskeletal tumor, using a pasteurized autogenous bone graft.

BACKGROUND: The pasteurized autogenous bone graft (PABG) is a new method to reuse resected and diseased autogenous bones after heat treatment at a comparatively low temperature (60 degrees C-65 degrees C). METHODS: The subjects of this study were ten patients with musculoskeletal tumor who underwent surgery with a PABG in the 6 years between 1995 and 2000. RESULTS: The pasteurized bone developed into bone union in all patients, except for the elderly patients who required repeat surgery. There were no infected patients. The PABG was performed by three different types of reconstruction, a segmental method, an intercalary method, and a combination method with an artificial joint as a spacer. No local recurrence of tumor the pasteurized bone was observed from in any patient. CONCLUSION: The PABG appears to be a comparatively easy, safe, inexpensive, and effective reconstruction method for musculoskeletal tumors. The pasteurized autogenous bone graft (PABG) is a new method to reuse resected and diseased autogenous bones after heat treatment at a comparatively low temperature (60 degrees C-65 degrees C).

Adolescent↗

PubMed1984

Bone scintigraphy in patients with operable breast cancer stages I and II. Final conclusion after five-year follow-up.

A 5-yr follow-up study was performed in 90 patients with stage I and II breast cancer who had a routine preoperative bone scan. The percentage of positive preoperative scans was 3.4%. Twenty-four of the 90 patients died within 5 yr. In all patients except five a follow-up scan was obtained. The results of our first study were confirmed. In only one of the three patients with a positive preoperative scan suspicious for bone metastases did bone metastases develop in this 5-yr follow-up study. One patient with an equivocal preoperative scan developed bone metastases. In 14 of the 16 patients with bone metastases and a positive scan in the follow-up period the preoperative scan was negative. From the preoperative and follow-up scan results we conclude that in stage I and II breast cancer there is no value in preoperative bone scanning. Routine bone scanning in the follow-up period appears to have little value in the asymptomatic patient.

Bone Neoplasms↗

PubMed2001

A novel fluorescent silica tracer for biological silicification studies.

BACKGROUND: Biological silica production has drawn intense attention and several molecules involved in biosilicification have been identified. Cellular mechanisms, however, remain unknown mainly due to the lack of probes required for obtaining information on live specimens. RESULTS: The fluorescence spectra of the compound 2-(4-pyridyl)-5-((4-(2-dimethylaminoethylaminocarbamoyl)methoxy)phenyl)oxazole (PDMPO) are affected by the presence of >3.2 mM silicic acid. Increase in intensity and shift in the fluorescence coincide with the polymerization of Si. The unique PDMPO-silica fluorescence is explored here to visualize Si deposition in living diatoms. The fluorophore is selectively incorporated and co-deposited with Si into the newly synthesized frustules (the outer silica shells) showing an intense green fluorescence. CONCLUSIONS: We suggest that a fluorescence shift is due to an interaction between PDMPO and polymeric silicic acid. PDMPO is an excellent probe for imaging newly deposited silica in living cells and has also a potential for a wide range of applications in various Si-related disciplines, including biology of living organisms as diatoms, sponges, and higher plants, clinical research (e.g. lung fibrosis and cancer, bone development, artificial bone implantation), and chemistry and physics of materials research.

Diatoms↗

PubMed1999

The effect of moderately and severely restricted dietary magnesium intakes on bone composition and bone metabolism in the rat.

Forty 3-week-old male rats, Wistar strain, average weight 59 g, were randomized by weight into five groups of eight rats each. Three groups were fed ad libitum on a semi-purified diet containing (per kg) 400 (adequate), 200 (moderately Mg-restricted) or 20 (severely Mg-restricted) mg Mg for 3 weeks while two groups were pair-fed with the Mg-adequate diet in the same quantities as those consumed by the two Mg-restricted groups respectively. While weight gains and food conversion efficiency values for the Mg-restricted groups were similar to those of the corresponding pair-fed control groups, serum and kidney Mg, and femoral dry weight were reduced by 70, 7 and 9% respectively in the severely Mg-restricted group and were unaffected in the moderately Mg-restricted group. Significant reductions were observed in urinary pyridinoline (Pyr) (by 44 and 34%) and deoxypyridinoline (Dpyr) levels (by 40 and 33%) (markers of bone resorption), serum osteocalcin levels (by 46 and 28%) (marker of bone formation), femoral Mg levels (by 52 and 14%) and osteocalcin mRNA levels (by 46 and 22%) compared with the corresponding pair-fed controls, in the severely and moderately Mg-restricted groups respectively, and these reductions, except for those in urinary Pyr and Dpyr, were more marked in the severely Mg-restricted group. Femoral Ca and P concentrations were unaffected by dietary Mg restriction. These results show that not only severe but also moderate dietary restriction of Mg over 21 d results in qualitative changes in bone (i.e. reduced Mg concentration) as well as in aberrant bone turnover in young growing rats (i.e. severely depressed rates of bone formation and bone resorption), which may impair bone development and bone strength.

Amino Acids↗

PubMed2000

Molecular structure and tissue distribution of matrilin-3, a filament-forming extracellular matrix protein expressed during skeletal development.

Matrilin-3 is a recently identified member of the superfamily of proteins containing von Willebrand factor A-like domains and is able to form hetero-oligomers with matrilin-1 (cartilage matrix protein) via a C-terminal coiled-coil domain. Full-length matrilin-3 and a fragment lacking the assembly domain were expressed in 293-EBNA cells, purified, and subjected to biochemical characterization. Recombinantly expressed full-length matrilin-3 occurs as monomers, dimers, trimers, and tetramers, as detected by electron microscopy and SDS-polyacrylamide gel electrophoresis, whereas matrilin-3, purified from fetal calf cartilage, forms homotetramers as well as hetero-oligomers of variable stoichiometry with matrilin-1. In the matrix formed by cultured chondrosarcoma cells, matrilin-3 is found in a filamentous, collagen-dependent network connecting cells and in a collagen-independent pericellular network. Affinity-purified antibodies detect matrilin-3 expression in a variety of mouse cartilaginous tissues, such as sternum, articular, and epiphyseal cartilage, and in the cartilage anlage of developing bones. It is found both inside the lacunae and in the interterritorial matrix of the resting, proliferating, hypertrophic, and calcified cartilage zones, whereas the expression is lower in the superficial articular cartilage. In trachea and in costal cartilage of adult mice, an expression was seen in the perichondrium. Furthermore, matrilin-3 is found in bone, and its expression is, therefore, not restricted to chondroblasts and chondrocytes.

Animals↗

PubMed2005

Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation.

Runx2 is a bone-specific transcription factor that plays a critical role in bone development, postnatal bone formation, and chondrocyte maturation. The protein levels of Runx2 are regulated by the ubiquitin-proteasome pathway. In previous studies we discovered that E3 ubiquitin ligase Smad ubiquitin regulatory factor 1 (Smurf1) induces Runx2 degradation in a ubiquitin-proteasome-dependent manner, and Smurf1 plays an important role in osteoblast function and bone formation. In the present studies we investigated the molecular mechanism of Smurf1-induced Runx2 degradation. Smurf1 interacts with the PY motif of substrate proteins, and a PY motif has been identified in the C terminus of the Runx2 protein. To determine whether Smurf1 induces Runx2 degradation through the interaction with the PY motif of Runx2, we created a mutant Runx2 with a PY motif deletion and found that Smurf1 retained some of its ability to induce the degradation of the mutant Runx2, suggesting that Smurf1 could induce Runx2 degradation through an indirect mechanism. Smurf1 has been shown to interact with Smads 1, 5, 6, and 7, and Smads 1 and 5 also interact with Runx2. In the present studies we found that Smads 1 and 5 had no effect on Smurf1-induced Runx2 degradation. Although Smads 6 and 7 bind Smurf1, it is not known if Smads 6 or 7 interacts with Runx2 and mediate Runx2 degradation. We performed immunoprecipitation assays and found that Smad6 but not Smad7 interacts with Runx2. Smad6 enhances Smurf1-induced Runx2 degradation in an ubiquitin-proteasome-dependent manner. These results demonstrate that in addition to its interaction with the PY motif of Runx2, Smurf1 induces Runx2 degradation in a Smad6-dependent manner. Smurf1-induced Runx2 degradation serves as a negative regulatory mechanism for the BMP-Smad-Runx2 signaling pathway.

Amino Acid Motifs↗

PubMed1976

Bone complications of anticonvulsants.

Anticonculsant drug-induced disorders in mineral and bone metabolism are apparently quite common. Current evidence indicates that these drugs derange bone metabolism, both through induction of increased hepatic catabolism of vitamin D and its biologically active products, as well as by direct effects on membrane cation transport systems. The significant clinical manifestions of the disorder include rickets with defective bone development, decreased bone mass with increased risk of pathological fracture and reductions in serum calcium levels which may predispose to increased seizure frequency. There is a broad range of clinical presentation with a number of factors -- drug dose, duration of therapy, vitamin D intake, amount of sunlight exposure, degree of physical activity and presence of other concurrent diseases -- which appear to determine the severity of the clinical manifestations. Current evidence indicates that appropriate vitamin D and calcium supplementation can significantly reduce the clinical manifestations of this disorder. All patients receiving chronic anticonvulsant drug therapy should be carefully evaluted for the presence of drug-induced osteomalacia and treated appropriately with vitamin D. This is especially important in those patients in whom the presence of multiple risk factors indicates an increased likelihood of deranged mineral metabolism.

Anticonvulsants↗