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PubMed1996

Increased expression of TGF-beta 2 in osteoblasts results in an osteoporosis-like phenotype.

The development of the skeleton requires the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts. The activities of these two cell types are likely to be regulated by TGF-beta, which is abundant in bone matrix. We have used transgenic mice to evaluate the role of TGF-beta 2 in bone development and turnover. Osteoblast-specific overexpression of TGF-beta 2 from the osteocalcin promoter resulted in progressive bone loss associated with increases in osteoblastic matrix deposition and osteoclastic bone resorption. This phenotype closely resembles the bone abnormalities seen in human hyperparathyroidism and osteoporosis. Furthermore, a high level of TGF-beta 2 overexpression resulted in defective bone mineralization and severe hypoplasia of the clavicles, a hallmark of the developmental disease cleidocranial dysplasia. Our results suggest that TGF-beta 2 functions as a local positive regulator of bone remodeling and that alterations in TGF-beta 2 synthesis by bone cells, or in their responsiveness to TGF-beta 2, may contribute to the pathogenesis of metabolic bone disease.

Age Factors↗

PubMed1992

Colocalization of thrombospondin and syndecan during murine development.

Thrombospondin is an adhesive glycoprotein that is thought to play a role in tissue genesis and repair. We have used a monoclonal anti-thrombospondin antibody, designated 5G11, to localize thrombospondin in paraformaldehyde fixed, paraffin-embedded sections of developing mouse embryos. Thrombospondin expression is observed in uterine smooth muscle, endometrial glands, the decidua, and trophoblastic giant cells during the initial phase of post-implantation development in the embryo. Cardiac myocytes and neuroepithelial cells show positive staining for thrombospondin at day 8.5 of gestation, and this expression continues throughout the development of the myocardium and central nervous system. Strong staining for thrombospondin is seen in developing bone and in the liver. Thrombospondin is also observed in developing smooth muscle and skeletal muscle, as well as in a variety of epithelia, including the epidermis, small intestinal epithelium, lens epithelium, renal tubular epithelium, and the epithelium of the developing tooth. Comparison of thrombospondin staining with that of two known cell surface receptors for thrombospondin, syndecan and the vitronectin receptor, reveals remarkable colocalization of thrombospondin and syndecan in all tissues, but almost no coexpression with the vitronectin receptor. Coexpression of thrombospondin and syndecan may play an important role in cell-cell or cell-matrix interactions during development.

Animals↗

PubMed1984

Calcitriol but no other metabolite of vitamin D is essential for normal bone growth and development in the rat.

To determine the relative importance of different metabolites of vitamin D in bone growth and development, weanling male rat pups suckled by vitamin D-deficient mothers were given either calcitriol (1,25-dihydroxycholecalciferol) by continuous subcutaneous infusion, oral calcidiol (25-hydroxycholecalciferol), or oral 24,24-difluoro-25-hydroxycholecalciferol, a synthetic compound that can undergo 1-hydroxylation but not 24-hydroxylation, as their sole source of vitamin D for 40 d. Pups raised in the same manner, but given no vitamin D, served as controls. The three metabolites compared were given in doses that restored normal plasma calcium levels and normal increments in body weight. After in vivo double tetracycline labeling, bone histomorphometry by standard methods was performed on one femur and one tail vertebra. There were no significant differences between the three metabolite-treated groups in length, periosteal or endosteal diameter, cortical cross-sectional area, cortical porosity, osteoid thickness and volume, appositional rate and bone formation rate in the femur, or in qualitative and quantitative indices of endochondral ossification in the tail vertebra. All three groups differed markedly from the untreated controls with respect to all measurements. Collectively, the data indicate that neither calcidiol nor any 24-hydroxylated metabolite of calcidiol is needed in the rat (other than as a precursor) for longitudinal or transverse bone growth, for normal endochondral ossification, or for normal periosteal and endosteal formation, mineralization, and resorption of bone. Calcitriol was fully active with respect to each of the indices listed when given in a manner resembling its continuous endogenous production by the kidney, suggesting that previous reports of incomplete skeletal response to calcitriol result from its rapid clearance and infrequent oral administration. We demonstrated that calcitriol is the only metabolite that is both necessary and sufficient for normal bone growth and development in the rat, but our data do not indicate the extent to which its beneficial skeletal effects were mediated by direct action on bone, either of calcitriol itself or of some metabolite thereof, or by restoration of normal plasma levels of calcium and phosphate.

Animals↗

PubMed1998

Species specificity of monoclonal antibodies to human tartrate-resistant acid phosphatase.

Tartrate-resistant acid phosphatase (TRAP) is expressed abundantly by osteoclasts and is required for bone resorption. This enzyme is emerging as an important biomarker in bone pathology, both for histochemical identification of osteoclasts and as a serum marker of osteoclast activity and increased bone turnover. Rat and mouse models are becoming popular systems for studying osteoclast development, bone physiology and morphogenesis, and bone diseases such as osteoporosis. We have developed two unique antibodies to human TRAP purified from hairy cell leukemia spleen. Both antibodies (9C5 and 14G6) are suitable for immunohistochemistry of osteoclasts and macrophages. Only one (14G6) is capable of immunoprecipitating active TRAP from human cell lysates. Antibody 9C5 reacts with a denatured epitope of TRAP while antibody 14G6 probably reacts with a native, conformational determinant. The high degree of homology among TRAPs of various species predicts that these antibodies should be suitable for work in experimental animals as well as humans. Immunohistochemical staining, electrophoretic analyses, immunoprecipitation and immunoblotting assays of human rat and mouse TRAP were carried out to test the validity of these antibodies as cell markers in rodents. Both antibodies were suitable for immunohistochemistry in all species. Antibody 9C5 was suitable for immunoblotting of denatured TRAP of all species tested. Antibody 14G6 reacted with the native TRAP of humans only and failed to immunoprecipitate mouse or rat TRAP activity. Although TRAP is a phylogenetically conserved protein, subtle, species-specific determinants exist. Care should be exercised when anti-TRAP antibodies are used for immunoassay in experimental animals.

Acid Phosphatase↗

PubMed2006

Effects of the LactoSorb bioabsorbable plates on the craniofacial development of rabbits: direct morphometric analysis using linear measurements.

The use of plates for the treatment of fractures can affect craniofacial bone development. This study investigated the effect of bioabsorbable plates and titanium microscrews on the growth of the craniofacial skeleton of rabbits (Oryctolagus cuniculus), in the neonatal period. A LactoSorb plate and PROMM titanium microscrews were positioned across the coronal suture in animals in the study group. In the control group, only PROMM titanium microscrews were attached to the cranium. Anteroposterior linear measurements were obtained using 3 different gauging devices: digital precision caliper, EKG caliper and nylon string. Frontal-nasal (FN) distances were statistically different between the left and right side when the digital caliper (P<or=0.01), EKG caliper (P<or=0.01) and nylon string (P<or=0.05) were used. Mean right-side FN distances in the control and study groups were significantly different (P<or=0.05) when measured with the EKG caliper. Normal neonatal craniofacial growth of rabbits was affected by the use of bioabsorbable plates in this study. Further studies should be conducted to investigate whether these plates affect growth in human beings.

Absorbable Implants↗

PubMed1999

A new member of tumor necrosis factor ligand family, ODF/OPGL/TRANCE/RANKL, regulates osteoclast differentiation and function.

Osteoclasts, the multinucleated giant cells that resorb bone, develop from monocyte-macrophage lineage cells. Osteoblasts or bone marrow stromal cells have been suggested to be involved in osteoclastic bone resorption. The recent discovery of new members of the tumor necrosis factor (TNF) receptor-ligand family has elucidated the precise mechanism by which osteoblasts/stromal cells regulate osteoclast differentiation and function. Osteoblasts/stromal cells express a new member of the TNF-ligand family "osteoclast differentiation factor(ODF)/osteoprotegerin ligand (OPGL)/TNF-related activation-induced cytokine (TRANCE)/receptor activator of NF-kB ligand (RANKL)" as a membrane associated factor. Osteoclast precursors which possess RANK, a TNF receptor family member, recognize ODF/OPGL/TRANCE/RANKL through cell-to-cell interaction with osteoblasts/stromal cells, and differentiate into osteoclasts in the presence of macrophage colony-stimulating factor. Mature osteoclasts also express RANK, and their bone-resorbingactivity is also induced by ODF/OPGL/TRANCE/RANKL which osteoblasts/stromal cells possess. Osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF)/TNF receptor-like molecule 1 (TR1) is a soluble decoy receptor for ODF/OPGL/TRANCE/RANKL. Activation of NF-kB and c-Jun N-terminal kinase through the RANK-mediated signaling system appears to be involved in differentiation and activation of osteoclasts.

Animals↗

PubMed1976

Effect of dialysate calcium concentration on bone disease in patients on hemodialysis.

Plasma biochemistry, bone radiology and morphometry were studied in a group of 20 patients receiving maintenance hemodialysis. The aim was to determine if increasing the dialysate calcium concentration would decrease plasma parathyroid hormone and improve the radiologic appearances of bone in patients without producing serious side effects. Dialysate calcium concentration was increased stepwise from 4.5 to 6.0 and then to 7.0 mg/100 ml. Mean predialysis plasma calcium concentration increased from 9.4 to 9.7 and then to 10.0 mg/100 ml and mean predialysis phosphate concentration increased from 5.3 to 5.6 mg/100 ml. Parathyroid hormone concentration was elevated in all patients but the mean concentration did not change significantly although in seven patients a decrease occurred. Six patients had radiologic signs of renal bone disease, two patients showed improvement and three patients developed bone disease during the study. The patients with radiologic bone disease had the highest parathyroid hormone concentrations and the majority were female. Morphometric bone measurements showed that bone loss during the study occurred mainly in the male patients. Soft tissue calcification continued to appear during the study. Although the response to some patients to an increased dialysate calcium concentration was favorable, it was impossible to predict which types of patient would benefit from the use of a dialysate calcium concentration of 7.0 mg/100 ml.

Adult↗

PubMed1999

Diaphyseal aclasis affecting the temporomandibular joint.

Diaphyseal aclasis is a rare disorder of bone development in which multiple, cartilagenous exostoses develop and enlarge mainly on the ends of long bones. It has also been described in the vertebral column where it may give rise to spinal cord compression but has not previously been reported as occurring in the jaws. A case is reported in which a patient known to suffer from diaphyseal aclasis at many other anatomical sites displays temporomandibular joint changes which are highly suggestive of the disease now manifesting in the jaws. The presentation, investigations and treatment are described and the literature concerning previous cases of diaphyseal aclasis is reviewed.

Adolescent↗

PubMed2001

Relation of ascorbic acid to bone mineral density and self-reported fractures among US adults.

Ascorbic acid is an essential nutrient involved in collagen formation, and its deficiency is associated with abnormal bone development. To examine the relation of ascorbic acid to bone mineral density and the prevalence of self-reported fractures, the authors analyzed data collected from 13,080 adults enrolled in the Third National Health and Nutrition Examination Survey (NHANES III) during 1988-1994. Because they identified three-way interactions among smoking, history of estrogen use, and dietary and serum ascorbic acid in postmenopausal women, they analyzed these relations stratified by smoking and estrogen use. Dietary ascorbic acid intake was independently associated with bone mineral density among premenopausal women (p = 0.002). Among men, serum ascorbic acid was associated in a nonlinear fashion with bone mineral density (p < 0.05), and dietary ascorbic acid intake was associated in a nonlinear fashion with self-reported fracture (p = 0.05). Among postmenopausal women without a history of smoking or estrogen use, serum ascorbic acid was unexpectedly associated with lower bone mineral density (p = 0.01). However, among postmenopausal women with a history of smoking and estrogen use, a standard deviation increase in serum ascorbic acid was associated with a 49% decrease in fracture prevalence (p = 0.001). Dietary and serum ascorbic acid measures were associated inconsistently with bone mineral density and self-reported fracture among adult participants in NHANES III.

Adult↗

PubMed1995

Radiotherapy alone compared with radiotherapy and chemotherapy in patients with squamous cell carcinoma of the esophagus.

PURPOSE: The purpose of this study is to determine whether primary treatment with both radiotherapy and chemotherapy is superior to radiotherapy alone in patients with squamous cell carcinoma of the esophagus. PATIENTS AND METHODS: From January 1980 to December 1988, 77 patients from two Veterans Affairs hospitals with clinically staged nonmetastatic squamous cell carcinoma of the esophagus received either radiotherapy alone (RT group) or concomitant radiotherapy and chemotherapy (RT + CT group) with curative intent. Each group originated at a different hospital, but all patients were irradiated in the same radiotherapy department. Chemotherapy consisted of cisplatin and 5-fluorouracil. Forty-two patients received RT alone, and 35 received RT + CT. Locoregional control, disease-free survival, and overall survival rates were compared. RESULTS: Locoregional control, disease-free survival, and overall survival rates were significantly higher in the RT + CT group when compared to RT group, 26% vs 5%, 20%, vs 2%, and 29% vs 7%, respectively, at 2 years (P = .01, 0.02 and 0.02, respectively). The median survival was 14 months for the RT + CT group and 7.5 months for the RT group. There was no difference in the incidence of distant metastases except for bone metastases. No one in the RT + CT group developed bone metastases compared to nine patients in the RT group (P = .01). CONCLUSION: This retrospective analysis shows improved locoregional control, disease-free survival, and survival when chemotherapy consisting of cisplatin and 5-FU is given in addition to radiation for patients with squamous cell carcinoma of the esophagus. Bony metastases were absent in those who received chemotherapy.

Aged↗

PubMed2002

Effect of HUVEC on human osteoprogenitor cell differentiation needs heterotypic gap junction communication.

Bone development and remodeling depend on complex interactions between bone-forming osteoblasts and other cells present within the bone microenvironment, particularly vascular endothelial cells that may be pivotal members of a complex interactive communication network in bone. Our aim was to investigate the interaction between human umbilical vein endothelial cells (HUVEC) and human bone marrow stromal cells (HBMSC). Cell differentiation analysis performed with different cell culture models revealed that alkaline phosphatase activity and type I collagen synthesis were increased only by the direct contact of HUVEC with HBMSC. This "juxtacrine signaling" could involve a number of different heterotypic connexions that require adhesion molecules or gap junctions. A dye coupling assay with Lucifer yellow demonstrated a functional coupling between HUVEC and HBMSC. Immunocytochemistry revealed that connexin43 (Cx43), a specific gap junction protein, is expressed not only in HBMSC but also in the endothelial cell network and that these two cell types can communicate via a gap junctional channel constituted at least by Cx43. Moreover, functional inhibition of the gap junction by 18alpha-glycyrrhetinic acid treatment or inhibition of Cx43 synthesis with oligodeoxyribonucleotide antisense decreased the effect of HUVEC cocultures on HBMSC differentiation. This stimulation could be mediated by the intercellular diffusion of signaling molecules that permeate the junctional channel.

Bone Marrow Cells↗

PubMed2004

Human primary endothelial cells stimulate human osteoprogenitor cell differentiation.

Bone development and remodeling depend on complex interactions between bone-forming osteoblasts and other cells present within the bone microenvironment, particularly endothelial cells that may be pivotal members of a complex interactive communication network in bone. While cell cooperation was previously established between Human OsteoProgenitor cells (HOP) and Human Umbilical Vein Endothelial Cells (HUVEC) the aim of our study was to investigate if this interaction is specific to Human Endothelial cell types (ECs) from different sources. Osteoblastic cell differentiation analysis performed using different co-culture models with direct contact revealed that Alkaline Phosphatase (Al-P) activity was only increased by the direct contact of HOP with human primary vascular endothelial cell types including endothelial precursor cells (EPCs) isolated from blood cord, endothelial cells from Human Saphen Vein (HSV) while a transformed cell line, the Human Bone Marrow Endothelial Cell Line (HBMEC) did not modify osteoblastic differentiation of HOP. Because connexin 43, a specific gap junction protein, seemed to be involved in HUVEC/HOP cell cooperation, expression by RT-PCR and immunocytochemistry of this gap junctional protein was investigated in EPCs, HSV and HBMEC. Both endothelial cells are positive to this protein and the disruption of gap junction communication using 18alpha-glycyrrhetinic acid treatment decreased the positive effect of these endothelial co-cultures on HOP differentiation as was previously demonstrated for HUVEC and HOP co-cultures. These data seem to indicate that this cross talk between HOP and ECs, through gap junction communication constitutes an additional concept in cell differentiation control.

Alkaline Phosphatase↗

PubMed2006

Mixed metastatic lung cancer lesions in bone are inhibited by noggin overexpression and Rank:Fc administration.

UNLABELLED: Lung cancer metastases to bone produce a primarily mixed osteolytic/osteoblastic lesion. The purpose of this study was to determine if blockade of both pathways would inhibit the formation these lesions in bone. Inhibition of the osteoblastic lesion with noggin and the osteolytic lesion with RANK:Fc was a successful treatment strategy to inhibit progression of mixed lung cancer lesions in bone. INTRODUCTION: Approximately 9-30% of patients with lung cancer develop bone metastases, leading to significant morbidity and mortality. A549 is a non-small-cell lung cancer (NSCLC) line that produces a mixed metastatic lesion in bone. We sought to determine if blockade of key components in both osteolytic and osteoblastic pathways would result in a reduction of a NSCLC tumor progression in a murine model of bony metastasis. MATERIALS AND METHODS: The study used a retroviral vector overexpressing noggin (RN), a specific inhibitor of BMP, and RANK:Fc, a chimeric protein that inhibits the RANK-RANKL interaction. A549 cells were transduced with RN before implantation in SCID mice. Cells were implanted in a subcutaneous model and tibial injection model. RANK:Fc was administered twice weekly at 15 mg/kg. There were five treatment groups: A549; A549 + RN; A549 + RANK:Fc; A549 + empty vector; and A549 + RN + RANK:Fc (n = 10/group). RESULTS: In SCID mice who underwent subcutaneous A549 tumor cell injection, animals treated with A549 + RN had significantly smaller subcutaneous tumor size at 8 weeks. In an intratibial model of bony metastasis, animals injected with A549 cells developed a mixed lytic/blastic lesion with cortical destruction at 8 weeks. Treatment with RANK:Fc inhibited the formation of osteoclasts, led to a smaller tumor volume in bone, and inhibited the lytic component of the mixed lesion. Animals treated with A549 + RN had a decreased number of osteoblasts in bone lesions, smaller tumor volume, and inhibition of the blastic component of the mixed lesions. Combination treatment inhibited both the lytic and blastic components of the lesion. CONCLUSIONS: The NSCLC cell line A549 forms a mixed osteolytic/osteoblastic lesion in vivo. Noggin overexpression inhibited the formation of the osteoblastic aspect of the lesion in bone and the tumor growth in vivo. Treatment with RANK:Fc limited the formation of the lytic aspect of the mixed lesion and also inhibited the rate of in vivo tumor growth. Inhibition of both pathways is necessary to effectively inhibit the progression of mixed metastatic lesions in bone.

Animals↗

PubMed1994

[Bone metastases from cancer of the cervix].

130 cases treated for cervical cancer developed bone metastases from 1958 through 1991, it was 0.87% of the total number of cervical carcinoma admitted to our hospital. (130/14,827). The rate of metastasis in each clinical stage was 0.85% (4/468) in stage I, 0.67% (41/6,064) in stage II, 0.97% (79/8,077) in stage III, 2.75% (6/218) in stage IV, respectively. Roentgenograms were diagnostic in all but 7 of the patients. The most common site of bone metastases was lumbar vertebrae, accounting for 44.69% of all bone metastases from cervix cancer. Metastases to pelvic bones ranked next. More than a half of the patients were diagnosed within 3 years after treatment. 86.92% of the patients died within 12 months, By now all patients were dead. Local radiation therapy was useful for pain relief but did not affect the prognosis.

Adult↗

PubMed1990

Radiographic determination of prenatal basicranial ossification.

In a previous investigation on prenatal development of the human cranial base, the sequence in which the bones develop in the midsagittal region was elucidated. The purpose of the present study was to identify fetal ossification on horizontal plane roentgenograms of the occipital and sphenoid bones in the central part of the cranial base, and establish stages in bone appearance related to general fetal developmental parameters. This study is based upon roentgenograms of the cranial base of 145 human fetuses from the first half of the prenatal period. Two different maturation patterns of the sphenoid bone were observed. The first, most common pattern is characterized by a midsagittal centre of ossification and the second by bilateral centres of ossification in the corpus of the sphenoid bone. These bilateral centres might in some cases be connected by a slight bony bridge. It appears that these different maturation patterns are maintained throughout the period investigated. The material was divided into five well-defined developmental stages for both maturation patterns and general parameters of fetal development. Mapping different aspects of ossification in normal cranial development is necessary for understanding deviations of cranial maturation and growth.

Gestational Age↗

PubMedDate not supplied

Skeletal disorders associated with skin pigmentation: a role of melatonin?

Although frequently encountered, no available consensus about the association between skeletal abnormalities and skin pigmentation. Several syndromes are characterized by the presence of skin pigmentation in association with skeletal disorders like neurofibroamtosis 1, McCune-Albright Syndrome, Jaffe-Campanacci Syndrome and Jaffe-Lichtenstein Syndrome. Even in the absence of these syndromes, skeletal abnormalities were detected in all radiologically examined patients having patterned skin pigmentation. Although skin pigmentation is controlled by several factors, melatonin is the most reliable factor to have relation to development of skeletal abnormalities. Recent research works support that melatonin might play a role in bone development and several hypotheses link melatonin with some bone diseases associated with skin pigmentation. It seems that melatonin deficiency is a probable operating co-factor in a lot of clinical situations characterized by skin pigmentation and skeletal disorders. This would explain some of the un-explained observations related to these syndromes and research works along these lines might lead to the development of efficient treatment for these diseases.

Bone Diseases↗

PubMed2003

Collagen XXIV, a vertebrate fibrillar collagen with structural features of invertebrate collagens: selective expression in developing cornea and bone.

Tissue-specific assembly of fibers composed of the major collagen types I and II depends in part on the formation of heterotypic fibrils, using the quantitatively minor collagens V and XI. Here we report the identification of a new fibrillar-like collagen chain that is related to the fibrillar alpha1(V), alpha1(XI), and alpha2(XI) collagen polypeptides and which is coexpressed with type I collagen in the developing bone and eye. The new collagen was designated the alpha1(XXIV) chain and consists of a long triple helical domain flanked by typical propeptide-like sequences. The carboxyl propeptide is classic, with 8 conserved cysteine residues. The amino-terminal peptide contains a thrombospodin-N-terminal-like (TSP) motif and a highly charged segment interspersed with several tyrosine residues, like the fibril diameter-regulating collagen chains alpha1(V) and alpha1(XI). However, a short imperfection in the triple helix makes alpha1(XXIV) unique from other chains of the vertebrate fibrillar collagen family. The triple helical interruption and additional select features in both terminal peptides are common to the fibrillar chains of invertebrate organisms. Based on these data, we propose that collagen XXIV is an ancient molecule that may contribute to the regulation of type I collagen fibrillogenesis at specific anatomical locations during fetal development.

Amino Acid Motifs↗

PubMed1978

Histochemical characterization of alkaline phosphatase in developing rat teeth and bone.

Alkaline phosphatase (EC 3.1.3.1.) in developing teeth and in bone has been studied. Prior to hard tissue function a rather high enzyme activity was noted in differentiating odontoblasts, stratum intermedium, and outer enamel epithelium. A lower activity was observed in the cells of the dental papilla and stellate reticulum. After the onset of hard tissue formation the alkaline phosphatase activity was generally increased. Enzyme activity was also found in the proximal part of tall, secretory ameloblasts. In the short postsecretory ameloblasts a high enzyme activity was noted. At the onset of dentin mineralization there was an increase in enzyme activity in the cells of the subodontoblastic layer. In bone the highest alkaline phosphatase activity was found in osteoblasts. A difference was noted between the alkaline phosphatase of hard and soft tissues by means of the addition of inhibitors to the incubation media. Within the hard tissues it was possible to distinguish between two alkaline phosphatases after pretreatment with heat (56 degrees C) or the addition of specific inhibitors (sodium metavandate, ortho-and pyrophosphate). An isoenzyme which was sensitive to these procedures was demonstrated in odontoblasts and in the pulpal connective tissue. Another alkaline phosphatase isoenzyme, which was resistant to pretreatment with heat or the addition of vanadate or phosphate, was demonstrated in the subodontoblastic cell layer, stratum intermedium and the outer cells of the reduced enamel epithelium.

Alkaline Phosphatase↗