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Biomedical subjects

S C Marks

Publications and source records attributed to S C Marks.

At least 163 records · Page 9Linked to original sources
PubMed1989

Osteoclast biology: lessons from mammalian mutations.

Major contributions to and confirmations of osteoclast biology have been made by experimental investigations of the osteopetrotic mutations in mammals. Congenital osteopetrosis is a bone disease characterized by a generalized increase in skeletal mass due to decreased osteoclast function. Abnormalities of skeletal growth and the failures of marrow cavity development and tooth eruption are secondary to reduced bone resorption of heterogeneous cause. Elucidation of pathogenetic pathways and unraveling of the cell biology of the osteoclast have proceeded hand-in-hand. This is illustrated by the variable differentiation and activation of osteoclasts among mutations and by demonstrations that the disease in certain animals and children can be cured by providing competent stem cells for osteoclasts via bone marrow transplantation. Congenital absence of carbonic anhydrase II (CA II) in children results in a syndrome that included osteopetrosis because osteoclasts are unable to function in the absence of CA II. The resistance of all mutations to the hypercalcemic effects of parathyroid hormone and recent reports of elevated blood levels of 1,25 dihydroxyvitamin D have broadened the scope of pathogenetic possibilities for osteopetrosis and regulatory possibilities for osteoclasts. Immunological effects including reductions in natural killer cell activity, superoxide and interleukin-2 production make osteopetrotic mutants potential models for studying the role of the immune system in osteoclast biology. Furthermore, coexistence of osteopetrosis with rickets and osteoblast abnormalities and the failure of cell transplants to cure the disease in some mutations illustrate the utility of the osteopetroses for exploring the role of matrix as mentor in osteoclast biology. Thus, understanding congenital osteopetrosis and osteoclast biology are likely to continue together.

Animals↗
PubMed1989

Treatment of congenital osteopetrosis in the rabbit with high-dose 1,25-dihydroxyvitamin D.

Osteopetrosis is a congenital metabolic bone disease characterized by skeletal sclerosis resulting from defective osteoclast-mediated bone resorption. Osteopetrosis has been described in several animal species (mouse, rat, and rabbit) and in children. Bone marrow transplantation, originally shown to reverse the skeletal sclerosis in some animal mutations, has been effective in curing osteopetrosis in some children. Unfortunately, not all children with osteopetrosis are candidates for or respond to bone marrow transplantation. Recent studies have shown that several animal mutations and some children inheriting osteopetrosis have significantly elevated serum levels of 1,25-(OH)2D. Based on the possibility that there may be a resistance to 1,25-(OH)2D, high-dose calcitriol therapy has been used to treat some children and stimulated some parameters of resorption. In this study, we have examined the effects of high-dose calcitriol therapy on various serum and skeletal parameters in the osteopetrotic rabbit. Mutant rabbits and normal littermates were given continuous infusions of calcitriol via subcutaneously implanted osmotic minipumps for 2 weeks at a dose of 0.5, 2.5, or 25 micrograms/kg/per day. Untreated mutant rabbits are hypocalcemic and hypophosphatemic in the presence of elevated serum 1,25-(OH)2 levels in comparison with their normal littermates. Calcitriol infusions resulted in dose-dependent increases in circulating 1,25-(OH)2D levels in both normal and mutant rabbits. However, evaluation of other serum parameters and the skeletal response demonstrated significant differences between osteopetrotic and normal rabbits. At the highest dose, normal animals rapidly became hypercalcemic and osteoporotic, accompanied by weight loss and a failure to thrive; mutants remained hypocalcemic and osteopetrotic but did not exhibit the deleterious physical effects seen in treated normal littermates. Although the number of osteoclasts increased in both mutants and normals, osteoclast phenotype in the former remained abnormal. These data indicate that although very high levels of circulating 1,25-(OH)2D were achieved in osteopetrotic mutants, activation of osteoclast-mediated bone resorption with subsequent improvement of skeletal sclerosis was not observed.

Animals↗
PubMed1989

Bone resorption in osteosclerotic mice is reduced in vitro.

Osteopetrosis in mammals results from a congenital reduction in bone resorption. Calvarial organ cultures were used to measure bone resorption in osteosclerotic (oc/oc) mice and their normal littermates. Measurements of cell-mediated resorption indicate that baseline isotope release by mutant calvariae was only 57% of that observed in normal littermates and isotope release by mutant bone in the presence of parathyroid hormone (PTH) was only 60% of that in normal controls. However, the response of oc calvariae to PTH was not different from normal bone when considered with respect to baseline resorption. These data indicate that bone resorption in oc mice is reduced in both its basal level and in response to PTH and suggest that oc mice are unable to establish normal baseline resorption which may in turn compromise their responsiveness to PTH.

Animals↗
PubMed1989

Calcitonin inhibits accumulation of cyclic AMP in stimulated peritoneal macrophages from normal rats but not from osteopetrotic (incisors-absent) littermates.

Macrophages and osteoclasts derive from related cell lines. In osteopetrotic mutants the function of osteoclasts is greatly reduced compared to that in normal animals or children and macrophage function is variably affected depending upon the mutation. To further explore macrophage function in osteopetrosis we examined the regulation of cyclic AMP production in macrophages from mutants and normal littermates of the osteopetrotic stock incisors-absent (ia) in the rat. Surface stimulation by latex particles of elicited peritoneal macrophages from normal or osteopetrotic (ia) mutant rats caused an identical increase in the accumulation of cyclic AMP. This effect was inhibited in normal animals by coincubation of macrophages with calcitonin (CT) but this inhibition was either absent or less marked in macrophages from mutant littermates. In contrast to human monocytes preincubation of rat macrophages with pertussis toxin did not relieve this inhibition. This implies that rat peritoneal macrophages respond to CT by a different mechanism. These results demonstrate altered macrophage function in osteopetrotic animals and may be functionally related to the reduced CT binding previously described in ia osteoclasts. Furthermore, the coexistence of reduced function of macrophages and osteoclasts in the ia mutation suggests that macrophages and osteoclasts share a common progenitor.

Animals↗
PubMed1989

Osteoclastic acid ATPase: biochemical and histochemical studies of the osteopetrotic mutations in the rat.

We have used a recently described acid ATPase assay in a histochemical and biochemical analysis of osteoclast development in the three osteopetrotic mutations in the rat where bone resorption is reduced but osteoclast numbers vary, depending upon the mutation. Enzymatic activity in bone was elevated in one mutation, severely reduced in another and moderately reduced in a third. Histochemical studies confirmed that the skeletal activity resided primarily in osteoclasts and showed that the enzyme activity in the mutation with moderately reduced levels was inversely distributed between osteoclasts and mononuclear cells. Enzyme activity in spleen, liver and peritoneal macrophages was not different in mutants and normal littermates. These results represent the first biochemical correlation of previous histochemical data and underscore the heterogeneity of osteopetrotic mutations. These data suggest that acid ATPase is a characteristic but not exclusive osteoclast marker which appears in skeletal sites late in osteoclast ontogeny.

Adenosine Triphosphatases↗
PubMed1989

Tartrate-resistant acid ATPase as a cytochemical marker for osteoclasts.

We present a modified histochemical method for staining osteoclasts and adjacent mononuclear cells which takes advantage of the recently described substrate specificity for ATP of osteoclastic acid phosphatase. Staining of osteoclasts using ATP as substrate exhibits by light microscopy the same tartrate resistance as conventional acidic phosphatases, without the bone surface staining seen with other substrates. This feature, coupled with specific staining of fewer vicinal mononuclear cells, makes this method potentially useful for studying osteoclast ontogeny and function.

Acid Phosphatase↗
PubMed1989

Proliferation and differentiation of osteoblasts in osteopetrotic rats: modification in expression of genes encoding cell growth and extracellular matrix proteins.

Osteopetrosis is characterized by a congenital defect in osteoclast differentiation and/or activity. The unresorbed matrix produces dense and sclerotic bone with the absence of a marrow cavity. Osteoblasts function in both the production and degradation of bone. However, the potential contribution of an osteoblast abnormality in the etiology of osteopetrosis has not been explored. We examined expression of cell growth-related genes (Core Hl histones and c myc) and genes related to osteoblast differentiation (Type I collagen, osteopontin and osteocalcin, an osteoblast-specific marker) in calvarial bone from the 3 osteopetrotic mutations in the rat (ia/ia, op/op and tl/tl) and normal littermates. mRNA preparations from these bones showed up to a 5-fold increase in all cell growth related genes in tl/tl and op/op rats, compared to normal littermates, suggesting a stimulation of proliferative activity of bone cells. The matrix genes also exhibited 2 to 10+fold increases in these two mutations. In contrast ia/ia rats showed no significant changes in expression of proliferation or matrix genes (except for osteopontin) which is consistent with the greatly reduced skeletal sclerosis in this mutation at the time (4 wk) when tissues were analyzed. Since the tl and op mutations have greater elevations in serum 1,25(OH)2D3 than found in the ia mutation, these results may reflect a stimulatory effect on cell proliferation and osteoblast activity by 1,25(OH)2D3. These data suggest that, in addition to osteoclast abnormalities, certain osteopetroses may also have aberrations of osteoblast function.

Animals↗
PubMed1988

Bone cell biology: the regulation of development, structure, and function in the skeleton.

Bone cells compose a population of cells of heterogeneous origin but restricted function with respect to matrix formation, mineralization, and resorption. The local, mesenchymal origin of the cells which form the skeleton contrasts with their extraskeletal, hemopoietic relatives under which bone resorption takes place. However, the functions of these two diverse populations are remarkably related and interdependent. Bone cell regulation, presently in its infancy, is a complicated cascade involving a plethora of local and systemic factors, including some components of the skeletal matrices and other organ systems. Thus, any understanding of bone cell regulation is a key ingredient in understanding not only the development, maintenance, and repair of the skeleton but also the prevention and treatment of skeletal disorders.

Animals↗
PubMed1988

Skeletal biology in the toothless (osteopetrotic) rat.

The toothless (tl) rat is a nonlethal osteopetrotic mutation characterized by the presence of few osteoclasts and the failure to be cured by bone-marrow transplantation. We examined the skeletal biology of tl rats and normal littermates up to 6 weeks after birth. Osteoclasts in tl rats were small, reduced 25-fold in number, and had greatly reduced concentrations of acid hydrolases. Bone shape internally and externally reflected reduced bone resorption, and tl rats were hypophosphatemic and mildly hypocalcemic at 2 weeks. These data indicate that the basic defect in tl rats is one of differentiation of osteoclasts and, coupled with the observation that normal bone-marrow cells cannot develop into osteoclasts in the tl skeleton, suggest that the defect lies in the skeletal micro-environment.

Animals↗
PubMed1988

Local infusion of prostaglandin E1 stimulates mandibular bone formation in vivo.

The maintenance of alveolar bone is a major clinical objective in dentistry. This is particularly difficult following such local inflammatory episodes as those of periodontitis or the loss of dentition (residual ridge resorption). We present evidence from beagle dogs that local infusion of prostaglandin E1 (PGE) for 3 weeks at doses of 500 to 2000 micrograms per week produces a dramatic, localized formation of alveolar bone in the mandible which exhibits a normal lamellar architecture and mineralization pattern when evaluated by fluorescence microscopy and microradiography. Whether this newly formed bone becomes functionally integrated into the skeleton and can replace bone lost from surgical resections or trauma remains to be established. Nevertheless, these data indicate that predictable local osteogenesis may eventually be produced by infusions of PGE.

Alprostadil↗
PubMed1988

Factors affecting visualization of posterior rib fractures in abused infants.

Rib fractures frequently are encountered in abused infants and commonly occur in the posterior rib arcs. Fractures occurring near the costovertebral articulations are rarely identified radiographically in the acute phase, and callus formation usually is the first indication of injury. To assess the factors influencing the visibility of fractures near the costovertebral articulations in abused infants, 103 posterior rib fractures occurring in 16 abused infants were studied radiologically. The plain radiologic studies were correlated with the pathologic findings in 15 ribs from four patients. The limited visibility of fractures relates to (1) the frequent superimposition of the transverse process over the rib fracture site, (2) a fracture line that crosses at an obliquity to the radiographic beam, and (3) nondisplacement of rib fragments due to preservation of the posterior periosteum. Fresh fractures invisible on a frontal projection are clearly defined when the rib is viewed axially with postmortem radiography. These findings explain the reported superior sensitivity of radionuclide bone scans vs radiography in the identification of fresh posterior rib fractures. A knowledge of the factors influencing the visibility of these important injuries is useful in planning an appropriate diagnostic evaluation in cases of suspected infant abuse.

Child Abuse↗
PubMed1988

Developmental changes in the extracellular matrix of the dental follicle during tooth eruption.

Eruption of the third and fourth mandibular premolars in the dog begins at 15 weeks of age, is dependent upon the dental follicle, and is complete by 23 weeks. Our study covered the period from 12 to 20 weeks, and revealed several changes in extracellular matrix structure and organization of the follicle which correlate with specific physiological events in eruption. First, the average DNA content per follicle reached a maximum at 14 weeks. Two weeks later, follicle size had increased 1.3- to 2.4- times. Second, the collagen content of follicles increased 2.5-fold over the study period, with two-thirds of this increase over the last four weeks. Type I collagen was the major collagen at all stages of follicular development. The amount of proteoglycan rose 45% from 16 to 20 weeks of age. Third, the ultrastructure of the dental follicle prior to eruption (12 weeks) indicated a disorganized interstitial connective tissue matrix; during eruption, two size classes of fibrils were observed which clustered together in linearly aligned bundles. Fourth, gel electrophoretic analyses resolved more than twenty follicle proteins with the major species a Mr = 95k glycoprotein. Immunoblotting demonstrated only one minor component was derived from serum. Comparison of noncollagenous proteins from different aged follicles indicated that three small polypeptides (Mr = 20-25 k) were present primarily at 16 weeks, the same time at which root elongation begins. A different sequence of changes was exhibited by two other proteins of Mr = 13 and 15 k. These findings may serve as biochemical markers of stages of dental follicle development and facilitate a search for local control mechanisms.

Aging↗
PubMed1988

Facies leprosa: resorption of maxillary anterior alveolar bone and the anterior nasal spine in patients with lepromatous leprosy in Mali.

Resorption of the anterior nasal spine and alveolar bone in the anterior maxilla was measured in 39 patients with lepromatous leprosy in Mali. Bone resorption occurred in both of these sites, but resorption in one did not predict resorption in the other. These data are interpreted to mean that resorptions of bone anterior (nasal spine) or inferior (alveolar bone) to bacillary populations in the nasal mucosa of patients with lepromatous disease in Mali occur independently.

Adolescent↗
PubMed1987

The osteopetrotic rabbit: skeletal cytology and ultrastructure.

The lethal, autosomal recessive osteopetrotic mutation in the rabbit, osteosclerosis (os/os), has recently been made available for experimental investigation. We have examined the cytology and ultrastructure of skeletal cells in mutants and report abnormalities in osteoblasts, osteocytes, and osteoclasts. Mutant osteoclasts lack a well-defined ruffled border and show few morphological signs of bone resorption. Osteoblasts in mutants form bone in neonatal life but show signs of degeneration by 2 weeks after birth. Mutant osteoblasts and osteocytes contain large, electron-dense cytoplasmic inclusions. External surfaces of mutant long bones show no evidence of bone resorption by scanning electron microscopy, and fibrosis of intertrabecular spaces is a prominent feature in mutants. These data, considered with recent evidence that the functions of osteoblasts and osteoclasts are interrelated, suggest that reduced bone resorption, a characteristic feature of osteopetrosis, may be related to osteoblast incompetence in this mutation.

Animals↗
PubMed1987

Congenitally osteosclerotic (oc/oc) mice are resistant to cure by transplantation of bone marrow or spleen cells from normal littermates.

The osteosclerotic mouse is a new, lethal recessive skeletal mutation which inherits osteopetrosis as an autosomal recessive. Affected mice are hypocalcemic and also have rickets. Osteoclasts are small and numerous with little evidence of function. This report examines the effects of bone marrow and spleen cell transplantation from normal littermates on survival and the radiographic appearance of the skeleton in 29 mutants. This procedure did not significantly prolong life or effect radiographic changes in the skeleton of most (27) recipients. However, two treated mutants lived for almost a year with radiographically normal skeletons. These variable responses to stem cell transplantation in an osteopetrotic mutant with rickets deserve further study.

Animals↗
PubMed1987

Failure of normal osteoclasts to resorb calcified cartilage from osteosclerotic (oc/oc) mice in vitro.

Osteosclerosis is an osteopetrotic mutation in the mouse characterized by reduced bone resorption, numerous small osteoclasts lacking elaborate ruffled borders, and resistance to cure by bone marrow transplants from normal littermates. The failure of osteosclerotic mice to be cured by bone marrow transplants could be due to the production of bone that is not resorbable by normal osteoclasts. We tested this hypothesis using a modification of the metatarsal organ culture system of Burger et al. (1982), in which metatarsals are cultured with various tissues that act as sources of osteoclast precursors. Metatarsals from neonatal mutants were isolated, and live bone rudiments were cultured with small cubes of liver or spleen from normal littermates for 7 days. Controls included normal and mutant metatarsals cultured alone or with spleen or liver from littermates of the same or different genotype. Mutant metatarsals cultured alone or with mutant tissue had small osteoclasts, no marrow spaces, and no evidence of bone resorption. Mutant metatarsals cultured with normal liver or spleen had larger osteoclasts, evidence of resorption of bone but not cartilage, and no marrow spaces because the calcified cartilage cores of metaphyseal trabeculae persisted. Normal metatarsals cultured with normal liver had large osteoclasts, bone resorption, and marrow spaces. By transmission EM, mutant trabeculae contained a layer of amorphous material between the central core of calcified cartilage and the surrounding bone matrix. This material was not present in normal metatarsals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Regional control by the dental follicle of alterations in alveolar bone metabolism during tooth eruption.

Tooth eruption is a localized, bilaterally symmetrical series of events which involves resorption and formation of alveolar bone on opposite sides of the tooth and requires the presence of the dental follicle. We examined the effect on eruption of selective surgical removal of parts of the follicle. Removal of either the basal or coronal halves of the follicle prevented eruption. Bone resorption and formation of an eruption pathway did not occur after removal of the coronal part of the follicle and bone formation did not occur after removal of the basal part of the follicle. Exposure and incisions of the follicle had no effect on eruption. We interpret these data to mean that the polarized resorption and formation of alveolar bone that occur around a tooth during eruption are regulated by the adjacent parts of the dental follicle.

Alveolar Process↗