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Biomedical subjects

M F Seifert

Publications and source records attributed to M F Seifert.

At least 37 records · Page 2Linked to original sources
PubMed1996

Maternal high calcium diet fails to reverse rickets in the osteosclerotic mouse.

The coexistence of osteopetrosis and rickets (osteopetrorickets) in humans has been described frequently. The osteosclerotic mouse is a unique, lethal osteopetrotic mutation that also has rickets. Attempts to cure this mutation by bone marrow transplantation have been largely unsuccessful, and its resistance to cure presumably is attributable to hypomineralized skeletal tissue that does not support osteoclast neogenesis, differentiation, and function. Current opinion regarding the clinical treatment of patients with osteopetrorickets involves first, the resolution of the rickets, followed by bone marrow transplantation to resolve the osteopetrosis, although this has not been successfully performed in humans. Attempts were made in the current study to reverse the rachitic lesion in the osteosclerotic mouse by feeding female breeders a high calcium (2.0%) diet throughout pregnancy and lactation. Mutant offspring (2 to 3 weeks of age) from such mothers remained hypocalcemic and hypophosphatemic, showed no decrease in growth plate cartilage thickness, and did not have enhanced cartilage or skeletal mineralization. For this unique mutation, efforts should be continued toward developing the appropriate therapies for reversal of its rachitic and skeletal defects; such therapies may yield insights into the clinical care of human infants with osteopetrorickets.

Animals↗
PubMed1995

Vitamin E stimulates trabecular bone formation and alters epiphyseal cartilage morphometry.

The effects of dietary vitamin E (VIT E) and lipids on tissue peroxidation and fatty acid composition, epiphyseal growth plate cartilage development, and trabecular bone formation were evaluated in chicks. A 2 x 2 factorial design was followed using two levels (30 and 90 IU/kg of diet) of dl-alpha-tocopheryl acetate and two different dietary lipids. The basal semipurified diet contained one of the following lipid treatments: anhydrous butter oil (40 g/kg) + soybean oil (60 g/kg), [BSO], or soybean oil (100 g/kg), [SBO]. After 14 days of feeding, the level of alpha tocopheryl in plasma was higher and thiobarbituric acid reactive substances (TBARS) were less in plasma and liver of chicks supplemented with 90 IU of VIT E compared with those given 30 IU of VIT E. Body weights and tibiotarsal bone lengths were not affected by the dietary treatments. Saturated fatty acids (14:0, 15:0, 16:0, 17:0, and 18:0) were increased in the tibiotarsal bone of chicks fed the BSO diet. In contrast, total polyunsaturated fatty acids and the ratio unsaturated fatty acids/saturated fatty acids were higher is plasma of chicks fed SBO compared with the values from chicks fed BSO. The thickness of the entire growth plate cartilage and the lower hypertrophic chondrocyte zone was significantly greater in chicks fed 90 IU/kg of VIT E. Kinetic parameters on bone histomorphometry indicated that mineral apposition rate was higher in chicks fed 90 IU of VIT E. The interaction effect between the VIT E and BSO treatments led to the highest trabecular bone formation rate among the groups. These data suggest that VIT E protects against cellular lipid peroxidation in cartilage to sustain normal bone growth and modeling.

Animals↗
PubMed1995

Eurysternum (extra-wide sternum)--a rarely recognized developmental anomaly. Scintigraphic appearances.

A rarely recognized extra-wide sternum was demonstrated by Tc-99m methylene diphosphonate bone scans in two adult patients. One patient was a 53-year-old man with prostate cancer who had no sternal symptoms or known sternal deformity. The second patient was a 41-year-old man with carcinoma of the lung whose extra-wide sternum was associated with a pectus excavatum deformity involving the lower half of the mesosternum (corpus sternum). A proper name for this developmental abnormality, "eurysternum" (eury-Greek word meaning broad; wide), is suggested. Two other patients, one with another type of wide sternum and another with a mesosternal foramen (fenestra sternii) deformity are also described. Related embryology and developmental anatomy of the sternum are reviewed.

Adult↗
PubMed1994

Lack of evidence for rickets in the osteopetrotic rat mutation, toothless.

A common, but paradoxic, feature among osteopetrotic human infants is the presence of rickets. This disorder of mineralization is manifested radiographically and histologically by increased growth plate cartilage and hypertrophic cell zone thickness and excess metaphyseal osteoid and biochemically by decreased serum calcium and phosphorus concentrations. Rickets has also been reported in two osteopetrotic animal mutations, the osteosclerotic (oc) mouse and the toothless (tl) rat. Although the phenotypic expression of the rachitic lesion in the oc mouse closely resembles that in affected humans, the results of the present study show that the lesion in the tl rat does not. Compared with normal littermates, histologic and morphometric analyses of tibial growth plate cartilage in tl rats up to 5 weeks of age showed age-related increases in thickness of the proliferative cell zone and decreases in thickness of the hypertrophic cell zone that were most apparent within the central, but not lateral, regions of the growth plate and areas of acellularity and failure of chondrocytes to transform synchronously from proliferative cell to hypertrophic cell phenotypes. Femoral ash content, composition, and accretion rates did not differ from those in normal rats during the first 5 weeks of life. These findings do not support the rachitic nature of the cartilage lesion in the tl rat. Rather, a chondrodysplastic disorder is suggested, which more closely resembles the cartilage defect present in this mutation.

Animals↗
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↗
PubMed1991

Long term effects of prenatal cocaine exposure on bone in rats.

Prenatal exposure to cocaine has been shown to produce a variety of effects on skeletal development and mineralization in humans, mice, and rats. The effects of cocaine on bone cell function and mineral metabolism pre- and postnatally are poorly understood. The present study examined the long term effects of prenatal cocaine exposure on femoral growth and mineralization in male rats. Pregnant rats were given 80 or 100 mg cocaine hydrochloride/kg during days 7-20 of gestation. At birth, body weights of pups born to these females were significantly decreased compared to normal and pair-fed controls. At the termination of the study (32 weeks), body weights of offspring from C100-treated females were still lower than normal. Long term effects of prenatal exposure to cocaine on femoral growth were most pronounced in offspring of C80-treated females. Femur dry weight, ash weight, organic matrix weight and density were significantly reduced in these animals compared to normal or pair-fed controls. The apparent osteopenic effects of prenatal exposure to cocaine suggests some long term postnatal impact on bone cell or mineral metabolism. Previous studies of cocaine use during pregnancy in humans and animals have focused primarily on physical and behavioral defects in offspring. The present findings indicate that prenatal exposure to cocaine may also have long term consequences to the skeleton.

Animals↗
PubMed1990

Elevated 1,25-dihydroxyvitamin D3 and intestinal calbindin-D9k in the toothless rat.

The toothless (tl) rat is a nonlethal osteopetrotic mutation characterized by systemic skeletal sclerosis, growth plate morphology suggestive of rickets, and morphological evidence of reduced osteoclastic bone resorption. Vitamin D metabolites, serum calcium and phosphorus levels, and the developmental appearance of vitamin D-dependent intestinal calcium binding protein (calbindin-D9k) was studied in normal and mutant rats of tl stock from 7 to 35 days of age. 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] was found to be significantly elevated in mutant animals by 7 days of age (71 +/- 9 pM, tl/tl vs. 24 +/- 8 pM, +/?) and continued to increase to a peak of 428 pM at the time of weaning. This was 240% higher than normals at this period. The elevated levels of 1,25-(OH)2D3 stimulated a significant and precocious appearance of intestinal calbindin-D9k in mutants, beginning by 14 days of age and reaching their peak levels at 21 days postpartum (25.6 +/- 1.7 micrograms/mg protein, tl/tl vs. 16.4 +/- 1.5 micrograms/mg protein, +/?). The cause of the elevated circulating levels of 1,25-(OH)2D3 in tl rats is unknown but may be due to the low serum phosphorus levels present in these animals.

Aging↗
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

Elevated levels of vitamin D-dependent calcium-binding protein (calbindin-D9k) in the osteosclerotic (oc) mouse.

The osteosclerotic (oc) mouse is an osteopetrotic mutation that has recently been identified as having rickets associated with its osteopetrosis. The presence of this rachitic lesion, unexplainable from a nutritional standpoint, prompted an investigation into the vitamin D endocrine system in these animals. The developmental appearance of vitamin D-dependent calcium-binding protein (calbindin-D9k) and alkaline phosphatase was studied in oc mutant and normal mice from birth to weaning, as were serum concentrations of 25-hydroxyvitamin D3 (25OHD3), 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], calcium, and phosphorus. Intestinal and renal calbindin-D9k levels were markedly and precociously elevated (4- to 9-fold) in young suckling, but not newborn, mutant mice compared to values in normal controls. Serum 25OHD3 levels were very low to undetectable in 2-week-old mutant mice compared to normal values, while 1,25-(OH)2D3 levels were 6 times higher in mutants. The exact cause of this premature induction in mutants is unknown, but may be due to elevated circulating levels of 1,25-(OH)2D. Alkaline phosphatase activity was similar between phenotypes at all ages. These studies indicate that the rachitic lesion present in oc mutants may be the result of some inherited disorder in vitamin D metabolism in these animals. Alternatively, these data are also consistent with a normal appropriate response to hypocalcemia and hypophosphatemia resulting from decreased osteoclastic bone resorption.

Aging↗
PubMed1988

Impaired macrophage migration in incisors absent (ia) osteopetrotic rats.

Thioglycollate was introduced into the peritoneal cavity of 32-, 50- and 80-day-old normal (ia/+) and incisor absent (ia/ia) osteopetrotic rats, and 3 days later macrophages were harvested. The number of macrophages recovered from 32- and 50-day-old ia rats was significantly less than that elicited from corresponding normal littermates. The macrophages from mutants also showed a significantly impaired ability to migrate in vitro. At 80 days, the number of macrophages obtained from ia rats was not significantly different from those elicited from control rats, and their migratory function was also close to those obtained from controls. The increase in macrophage number and migrating capacity noted in 80-day-old ia rats correlates with increased marrow development at this age as described by Marks (Pathogenesis of osteopetrosis in the ia rat. Reduced bone resorption due to reduced osteoclast function, Am. J Anat 1973;138:165-190.

Animals↗
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↗
PubMed1986

Bone particles from osteopetrotic mice not cured by bone marrow transplants are resorbed in normal littermates.

Osteosclerotic (oc/oc) and osteopetrotic (op/op) mice are not cured by bone marrow transplantation from normal littermates. The possibility that this is due to production of poorly resorbable bone was examined by comparing the fate of mutant and normal bone particles implanted subcutaneously in normal hosts. Bone, removed aseptically from calvarial and tibial sites of normal littermates and mutants, was cleaned of adherent soft tissue, ground and sieved to a particle size of 70-300 micron. Aliquots (17-20 mg) of bone from each phenotype of each stock were pelleted and implanted beneath the anterior thoracic skin of normal littermates for two weeks. Particle density in tissue sections was determined as percent of field by a point-counting method. Giant cell response was recorded as number per high-power field. Percent bone present initially was determined in pellets implanted for less than 24 hr. Bone particles were reduced in each pellet with time, about 25% of the original volume being removed in two weeks. No statistically significant differences were noted in the rates of disappearance of mutant and normal bone or in the percentage or number of giant cells in implants of mutant and normal bone in either stock. Furthermore, these values were not different from identical studies in microphthalmic mice, an osteopetrotic stock cured by bone marrow transplantation. These data suggest that the failure of osteopetrotic and osteosclerotic mice to be cured by bone marrow transplants from normal littermates is not due to the presence of unresorbable bone.

Animals↗
PubMed1986

The osteopetrotic rabbit: general and skeletal features of a new outbred stock.

Stock of the lethal osteopetrotic mutation in the rabbit has been outbred to robust New Zealand White stock. Features of this new stock include skeletal sclerosis and failure of tooth eruption characteristic of osteopetrosis, together with hypocalcemia, hypophosphatemia, and osteoclasts of reduced numbers and abnormal cytology. No abnormalities of carbonic anhydrase II were detectable by electrophoresis. The commercial availability of mutants of this new stock makes them a potentially important source of information about both osteopetrosis and osteoclast biology.

Animals↗
PubMed1985

Morphological evidence of reduced bone resorption in the osteosclerotic (oc) mouse.

Osteopetrosis, a metabolic bone disease characterized by a generalized sclerosis of the skeleton, is inherited as an autosomal recessive in a number of mammalian species. The pathogenesis of congenital osteopetrosis is mediated by a reduction in bone resorption as a result of decreased osteoclast function. This hypothesis is based on both functional and structural evidence of reduced bone resorption in all mutations examined to date. The present study examined the histology of cartilage and bone, the ultrastructure of osteoclasts, and the morphology of mineralized bone surfaces in a lethal osteopetrotic mutation, the osteosclerotic (oc) mouse. Histologically, epiphyseal cartilage growth plates, especially the hypertrophic zone, are markedly thickened in oc mice and metaphyses contain excessive osteoid, features characteristic of rickets. Transmission electron microscopy revealed that less than one-quarter of osteoclasts in oc mice demonstrated evidence of ruffled border formation compared with three-quarters of the osteoclasts in normal littermates. In mutants, ruffled borders were less elaborate and cytoplasmic processes penetrated into bone surfaces, suggesting that bone may be removed by mechanical rather than by enzymatic means. There was little morphological evidence of cartilage degradation and broad laminae limitantes persisted in mutants. Mineralized surfaces that undergo resorption in normal mice showed no evidence of bone resorption by scanning EM in mutants. The presence of a rachitic condition, the observations of reduced bone resorption, and the possible contribution of undermineralized matrices to decreased bone resorption are characteristics of the osteosclerotic mutation which suggest that it is a unique osteopetrotic mutant in which to study both the development and regulation of skeletal metabolism.

Animals↗
PubMed1985

The lifespan of osteoclasts: experimental studies using the giant granule cytoplasmic marker characteristic of beige mice.

Osteoclasts are large multinucleated skeletal cells that form by fusion of bloodborne mononuclear precursors. Fusion with mononuclear precursors occurs throughout life, and survival of osteoclasts is believed to be dependent upon continued replenishment by fusion. This study examined osteoclast lifespan, defined as maximal survival without fusion, in normal mice irradiated to eliminate host stem cells and rescued with stem cells from beige (bg) mice whose osteoclasts have a distinctive phenotype. Osteoclasts of donor phenotype appeared during the second week and progressively increased so that by the sixth week no osteoclasts of host phenotype were present. Radiation alone did not produce any change in osteoclast phenotype. These data are interpreted to indicate that the maximal survival of osteoclasts without fusion of precursors is less than 6 weeks.

Animals↗
PubMed1985

Rickets and osteopetrosis: the osteosclerotic (oc) mouse.

A new mouse osteopetrotic mutation, osteosclerosis, has been examined with respect to rickets. These osteopetrotic mice were hypocalcemic and hypophosphatemic, and had greatly thickened epiphyseal plates with abnormalities in matrix vesicles when compared with normal littermates. Such biochemic and morphologic manifestations of rickets in this osteopetrotic mutation may explain the failure of osteosclerotic mice to be cured by transplantation of bone marrow from normal littermates and indicate that vitamin D metabolism and matrix vesicle biochemistry warrant further study.

Animals↗