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S C Marks

Publications and source records attributed to S C Marks.

At least 127 records · Page 7Linked to original sources
PubMed1994

Transcriptionally active nuclei isolated from intact bone reflect modified levels of gene expression in skeletal development and pathology.

Transcriptional regulation of gene expression in vivo in bone, associated with normal development or skeletal disorders, to date, has not been studied. We report the successful isolation of nuclei that are transcriptionally active from normal and osteopetrotic rat bone. Transcription rates of cell growth and bone-related genes (including histone H4, c-fos, c-jun, TGF beta 1, beta 2 macroglobulin, collagen, fibronectin, osteocalcin, osteopontin, and tartrate resistant acid phosphatase) change as a function of calvarial development from birth to 6 weeks and are selectively modified in osteopetrotic animals. Additionally, nuclei isolated from intact bone yield promoter binding factors. Bone nuclei, which transcribe faithfully and contain the normal complement of nuclear protein factors, offer a powerful approach for investigating in vivo gene regulation in skeletal development and pathology.

Animals↗
PubMed1994

Aberrant gene expression in cultured mammalian bone cells demonstrates an osteoblast defect in osteopetrosis.

Osteopetrosis is a skeletal condition in which a generalized radioopacity of bone is caused by reduced resorption of bone by osteoclasts. However, it has recently been shown that during skeletal development in several osteopetrotic rat mutations specific aberrations occur in gene expression reflecting the activity of the bone forming cells, osteoblasts, and the development of tissue organization. To evaluate their pathogenetic significance, progressive osteoblast differentiation was studied in vitro. Primary cultures of normal osteoblasts undergo a sequential expression of cell growth and tissue-related genes associated with development of skeletal tissue. We report that osteoblast cultures can be established from one of these mutants, toothless; that these cells in vitro exhibit similar aberrations in gene expression during cell proliferation and extracellular matrix formation and mineralization observed in vivo; and that an accelerated maturation sequence by mutant osteoblasts mimics the characteristic skeletal sclerosis of this disease. These data are the first direct evidence for an intrinsic osteoblast defect in osteopetrosis and establish an in vitro model for the study of heritable skeletal disorders.

Animals↗
PubMed1994

Understanding bone cell biology requires an integrated approach: reliable opportunities to study osteoclast biology in vivo.

The relative simplicity of all in vitro methods to study bone cell biology will at best result in oversimplification of the development and functional capacity of the skeleton in vivo. We have shown this to be true for selected aspects of bone cell biology, but numerous other examples are available. One alternative is to undertake skeletal research in vivo. It is important that those in bone research be willing to move increasingly in this direction not only to understand the true complexities of skeletal versatility, but also to avoid repetition and perpetuation of erroneous or irrelevant conclusions which waste resources. Toward this end we have described two situations, osteopetrosis and tooth eruption, in which reproducible abrogations or local activations of bone resorption can be examined in vivo. The application of emerging molecular and morphological techniques that permit the subcellular dissection of metabolic pathways and their precise cellular localization, such as a combination of the variety of in situ hybridization technologies with PCR, antisense probes, and antibody blockase, will allow the investigator greater control of variables in vivo. We expect that these technologies, largely worked out in vitro, combined with highly selected, appropriate models, as we have ourlined here for osteoclast biology, will make research in vivo less intimidating and increase the frequency with which the real biology is studied directly.

Animals↗
PubMed1994

Abnormalities of phosphoprotein gene expression in three osteopetrotic rat mutations: elevated mRNA transcripts, protein synthesis, and accumulation in bone of mutant animals.

Osteoclast abnormalities that characterize osteopetrosis, a disorder of bone resorption, may derive from aberrant signals from the osteoblast or the bone matrix. In the present studies, both synthesis and the bone matrix content of the major bone phosphoprotein component, osteopontin, were found to be elevated in three osteopetrotic rat mutations (ia, op, and tl). In whole bone, a twofold increase in the content of the characteristic amino acid O-phosphoserine for osteopontin occurred in op and tl mutant long bone, but a smaller (15%) and more variable increase was observed in ia mutant rat long bone. Extraction of the bone matrix components and partial purification by reverse phase chromatography showed a twofold increase in a phosphoprotein fraction relative to other noncollagenous components. Amino acid analysis and staining characteristics of SDS-PAGE fractionated proteins indicated this to be osteopontin. Organ cultures of calvarial bone from 4 day ia osteopetrotic mutant and normal rats in the presence of 3H-proline showed increased synthesis of this 60 kD protein, which was stimulated by vitamin D. Preparation of total cellular RNA from bone of 2- and 6-week-old mutants and normal rats supported increased synthesis of osteopontin as reflected by hybridization with osteopontin cDNA probe, showing significantly higher levels of mRNA transcripts in ia (3-5 fold), tl (1.4-2 fold), and op (6-25 fold) mutant bone compared to normal littermates. The changes in osteopontin mRNA levels in mutant bone were also examined in relation to other growth and phenotype-expressed genes. The findings of increased accumulation of osteopontin in osteopetrotic bone and increased synthesis by osteoblasts are interesting in light of the previously reported decrease in bone osteocalcin content (Endocrinology, 126:966, 1990), confirmed here by decreased osteocalcin mRNA transcripts. Such aberrations in the composition of skeletal extracellular matrix could be a reflection of or a contributing factor to the osteoclast abnormalities of some of these osteopetrotic disorders.

Animals↗
PubMed1994

Bone mineral density in the femur and lumbar vertebrae decreases after twelve weeks of diabetes in spontaneously diabetic-prone BB/Worcester rats.

The accumulated data indicate that bone mineral density (BMD) is decreased in humans with insulin-dependent diabetes mellitus. The purpose of this study was to prospectively determine sequential lumbar and femoral BMD utilizing dual energy X-ray absorptiometry in rats that spontaneously become diabetic to determine if weight and blood glucose control would prevent the diabetes-related bone mass changes. BMD of the lumbar spine and femur was measured prior to the onset of diabetes and at 3-week intervals after the diagnosis of diabetes for 12 weeks in 14 diabetes-prone BB/Wor rats (DP) and eight diabetes-resistant BB/Wor control rats (DR). At 12 weeks, the lumbar (0.238 +/- 0.013 vs 0.262 +/- 0.007 g/cm2, P < 0.001) and femoral (0.313 +/- 0.013 vs 0.343 +/- 0.013 g/cm2, P < 0.001) BMD were significantly lower in the DP rats despite significantly greater body weights (387 +/- 26 vs 329 +/- 46 g, P < 0.001) and plasma glucose levels of only 178 mg/dl. There was no difference in plasma values of calcium, phosphorus, osteocalcin, or tartrate-resistant acid phosphatase between groups or differences in osteoblast numbers in histologic sections. There was a significant (P < 0.001) decrease in plasma creatinine in the diabetic animals. The results indicate that in this animal model of type I diabetes, spine and femoral BMD do not increase comparable to control despite weight and blood glucose control. This would suggest that the diabetic condition itself affects bone mass in the absence of weight loss and poor blood glucose control.

Absorptiometry, Photon↗
PubMed1994

Dental abnormalities in the osteopetrotic rat mutation microphthalmia blanc.

Dental manifestations of the mild, transient osteopetrosis in the rat mutation microphthalmia blanc (mib) were examined. Eruption of all teeth was delayed in mib rats compared to normal littermates. The delays ranged from 5 days for incisors to 3 and 2 days for the first and second molars. Normal rats had straight incisors in the sagittal plane that exhibited signs of wear, but in mib littermates the incisors were maloccluded, distorted, and showed no signs of wear. Radiographic and histological examination of the dentition of 1- and 4-week-old rats revealed that the apical end of incisors in mib rats failed to extend posteriorly to the third molar region as in normal siblings, but ended at the first molar. Histological examination of longitudinal sections of mandibles through the incisors of neonatal normal and mib rats showed that in 1-day-old mutants the incisor was closely surrounded by alveolar bone to which it was ankylosed. The incisor body in mib rats was also malformed, with an indented apical end. This ankylosis was temporary, being resolved by 3 days. These findings show that neonatal reductions in bone resorption cause incisor defects and delay the eruption of all teeth in mib rats. The malocclusion and distortion of incisors of mib rats are likely caused by temporary ankylosis of incisor matrices to alveolar bone. Taken together, these findings illustrate the concept that bone resorption is an essential and rate-limiting element of tooth eruption.

Animals↗
PubMed1994

The effect of removing the true dental follicle on premolar eruption in the dog.

Eruption is a highly localized process during which the bone resorption and formation that occur on opposite sides of the tooth are dependent upon the surrounding soft tissues, the true dental follicle externally and the enamel organ internally. To examine the ability of the enamel organ to cause eruption the external layer (dental follicle) was removed just prior to and up to 4 weeks before eruption in 13 mandibular premolars in dogs and eruption followed clinically, radiographically and histologically. None of the teeth without dental follicles erupted but three teeth from which the follicle was separated then replaced did erupt. These data indicate that the enamel organ without the dental follicle cannot support tooth eruption and provide indirect evidence for the central role of the dental follicle, alone or in combination with the enamel organ, in eruption.

Animals↗
PubMed1994

Local delivery of prostaglandin E1 induces periodontal regeneration in adult dogs.

Formation of cementum, alveolar bone and periodontal ligament was produced in 18 sites on buccal surfaces of mandibular premolars and molars of 11 adult dogs near to sites of local delivery of prostaglandin E1 (PGE) for three weeks. Mineralizing bone and cementum were labelled with fluorescent dyes and polarizing microscopy showed periodontal ligament fibers between these new mineralized tissues. These observations extend recent demonstrations that local application of PGE causes formation of new bone on the mandible and suggest the potential for predictable, site-directed periodontal regeneration.

Alprostadil↗
PubMed1994

Carotid artery reconstruction using superficial femoral arterial grafts.

The indications, consequences, and value of resection of the carotid artery as part of an extended neck dissection has been discussed for many years. Many of the earlier reports have focused on the sequelae of carotid artery ligation and tests to predict patient tolerance for the procedure. Efforts to reconstruct the carotid artery have been limited primarily to vein grafts. The authors report on 11 cases of reconstruction of the carotid artery using the patient's superficial femoral artery. The femoral artery itself is reconstructed using a Gore-Tex graft. Free autografts of the superficial femoral artery in the carotid location have been found to be an excellent size match, mechanically stronger than a vein graft, and tolerant of bacterial contamination. Arteriography in 1 case with 14 months' follow-up demonstrates long-term patency.

Blood Vessel Prosthesis↗
PubMed1994

Cortical bone osteocalcin content and matrix composition in autosomal dominant osteopetrosis type I.

Several bone matrix protein constituents, including the major component collagen type I and the hydroxyapatite binding protein, osteocalcin, have been implicated in the regulation of bone turnover. Cortical bone osteocalcin, collagen and mineral content were studied in autosomal dominant osteopetrosis type I (ADO), a disorder characterized by diffuse symmetrical osteosclerosis. Iliac crest bone biopsies were obtained from eight patients (mean age 43.0 years, range 17-63 years) and compared with 16 age- and sex-matched normal controls (mean age 44.1 years, range 20-61 years). The osteocalcin level in cortical bone was increased (p < 0.03) in ADO (51.4 +/- 3.9 mg/kg bone) compared with controls (38.0 +/- 3.6 mg/kg bone). Total collagen, protein and calcium expressed per kilogram bone dry weight were without significant difference between patients and controls. The pathogenesis of ADO is most likely not related to cortical bone osteocalcin content, a protein implicated in osteoclast ontogeny and activation. These observations are in contrast to recent observations of reduced bone osteocalcin levels in osteopetrotic mutations in the rat and underscore the interspecies heterogeneity of this disorder.

Adolescent↗
PubMed1994

A longitudinal study of alveolar bone loss around maxillary central incisors in patients with leprosy in Malaysia.

The loss of alveolar bone supporting the maxillary central incisors and the general periodontal conditions were evaluated after 14 years in the 12 patients remaining from an original group of 47 under treatment in Malaysia. Alveolar bone loss was minimal during this period even in the presence of periodontal inflammation. These data suggest that treatment protects patients with leprosy from alveolar bone loss and suggests that other skeletal deformities might respond similarly.

Adult↗
PubMed1994

Effects of prostaglandins on the skeleton.

Prostaglandins (PGs), particularly those of the E series, have potent effects on bone resorption in vitro and on bone formation, bone remodeling, and bone modeling in vivo. When given systemically, PGEs have powerful anabolic effects--increasing bone formation rates, bone modeling in the formation mode, and remodeling with a net increase in bone mass. When applied locally, PGE1 increases periosteal bone formation and alveolar bone mass, and appears to promote periodontal soft-tissue regeneration. PGs have potential clinical application in the local restoration or augmentation of bone mass, focal stimulation or bone formation, and the regeneration of soft tissues associated with osseous tissues, such as fibrous and ligamentous insertions into bone.

Animals↗
PubMed1993

Defective pro alpha 2(I) collagen synthesis in a recessive mutation in mice: a model of human osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue associated with fractures, osteopenia, and short stature. OI results from mutations affecting the pro alpha 1 or pro alpha 2 gene of type I collagen. We describe a strain of mice with a nonlethal recessively inherited mutation (oim) that results in phenotypic and biochemical features that simulate moderate to severe human OI. The phenotype of homozygous oim mice includes skeletal fractures, limb deformities, generalized osteopenia, and small body size. Their femurs are smaller and demonstrate marked cortical thinning and fewer medullary trabeculae than those of wild-type mice. Breeding studies show the mutation is inherited in most crosses as a single recessive gene on chromosome 6, near the murine Cola-2 gene. Biochemical analysis of skin and bone, as well as isolated dermal fibroblast cultures, demonstrate that alpha 1(I) homotrimeric collagen accumulates in these tissues and is secreted by fibroblasts. Short labeling studies in fibroblasts demonstrate an absence of pro alpha 2(I) collagen chains. Nucleotide sequencing of the cDNA encoding the COOH-propeptide reveals a G deletion at pro alpha 2(I) nucleotide 3983; this results in an alteration of the sequence of the last 48 amino acids. The oim mouse will facilitate the study of type I collagen-related skeletal disease.

Amino Acid Sequence↗
PubMed1993

Indications for open surgical removal of airway foreign bodies.

Airway foreign bodies can usually be extracted by skillful application of endoscopic techniques. We report our experience in the management of 2 infants in whom sharp, pointed objects dictated consideration for an open surgical approach. Clinical presentation and treatment options will be discussed in the successful management of these 2 patients, one with a crab claw in the subglottis and the other with an electronic diode in the lung. Extensive training and a full complement of modern instruments are required, but in highly selected cases, an open surgical procedure entails less risk than endoscopic extraction.

Airway Obstruction↗
PubMed1993

Experimental studies of osteopetrosis in laboratory animals.

Osteopetrosis is a metabolic bone disease characterized by a systemic increase in skeletal mass. It results from a defect in the production or function of osteoclasts and is inherited in nine genetically distinct osteopetrotic animal mutations and man. Studies of these mutations have revealed that osteopetrosis is a complex, heterogeneous disorder in its expression, etiology, and response to treatment by bone marrow transplantation or by hormone/growth factor therapy. These animal mutations have been valuable tools for probing the pathogenesis and treatment of osteopetrosis, and information obtained from these studies has been used clinically for the treatment of humans with osteopetrosis. In addition, studies of these mutations have contributed significantly to understanding normal bone cell biology, including the origin of the osteoclast and the significance of colony-stimulating factor-1 in osteoclast development. The resistance of some of these mutations to cure by stem cell transplantation and hormone therapy, coupled with similar observations and experiences in the human condition, indicates that these animal mutations will continue to serve important roles in the development of alternative therapies to treat resistant forms of the disease. These studies are bound to improve the understanding of normal bone biology by providing additional insights into the regulation of osteoclasts by osteoblasts and their products or by other elements of the skeletal microenvironment.

Animals↗
PubMed1992

The effects of colony-stimulating factor-1 on tooth eruption in the toothless (osteopetrotic) rat in relation to the critical periods for bone resorption during tooth eruption.

The toothless (tl) rat is an osteopetrotic mutation characterized by a generalized skeletal sclerosis, reduced bone resorption, few osteoclasts and a total absence of erupted teeth. This mutation is not cured by bone marrow transplants from normal littermates. It is known that the skeletal defects in tl rats are greatly improved after treatment with colony-stimulating factor-1 (CSF-1). This investigation concerns the effects of CSF-1 on the development and eruption of the dentition of tl rats. Untreated tl rats had no erupted teeth by 56 days after birth, and the roots of incisors and molars were severely distorted by compression against bone. The apex of the mandibular incisor did not extend past the first molar and continued growth of its apical end produced odontoma-like masses consisting of distorted dentine and enamel matrices. In addition, few osteoclasts were seen on alveolar bone surfaces surrounding the developing teeth. Mutants given CSF-1 were characterized by delayed eruption of all molars and sometimes incisors. The incidence of incisor eruption was related inversely to the age at which CSF-1 treatment began. Molars of treated tl rats had well-developed roots similar to those in normal rats. Treated mutants had numerous osteoclasts in alveolar bone and well-developed haemopoietic marrow spaces in the mandible. Histochemical staining for both tartrate-resistant acid phosphatase and tartrate-resistant acid ATPase was reduced or negligible in osteoclasts of untreated tl rats, heavy in normal osteoclasts and of intermediate intensity in CSF-1-treated mutants.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Administration of colony stimulating factor-1 corrects some macrophage, dental, and skeletal defects in an osteopetrotic mutation (toothless, tl) in the rat.

The toothless (tl/tl) mutation in the rat results in a paucity of osteoclasts and osteopetrosis that cannot be corrected by bone marrow transplantation. In the present study we demonstrate that tl/tl rats also have profound deficiencies of femoral, peritoneal, and pleural cavity macrophages. Furthermore, the macrophage colony stimulating activity of post-endotoxin sera from tl/tl rats is substantially reduced, suggesting that, as in the case of the op mutation in mice, the basis of the tl mutation is a deficiency of the macrophage growth factor, colony stimulating factor-1 (CSF-1). Consistent with this suggestion, treatment of tl/tl rats from birth for up to six weeks with CSF-1 reduced the osteopetrosis, increased body weight, and permitted tooth eruption. In addition, CSF-1 treatment induced large numbers of osteoclasts in tl/tl bones and macrophages in the peritoneal cavity and bone marrow. Persistence of metaphyseal sclerosis, however, indicated that the disease was not totally corrected by this treatment. These studies indicate that the basis of the tl mutation is most likely another CSF-1 deficiency, and further emphasize the role of this growth factor in osteoclast differentiation.

Animals↗