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Biomedical subjects

M F Seifert

Publications and source records attributed to M F Seifert.

At least 19 recordsLinked to original sources
PubMed2001

Lipids as modulators of bone remodelling.

Bone remodelling processes are regulated by systemic hormones and a multitude of local and systemic factors, including prostaglandins, cytokines, and growth factors. Dietary fatty acids and their derivatives (eicosanoids) have been a recent focus of investigation on bone and cartilage metabolism. Specific fatty acids are recognized modulators of eicosanoid biosynthesis, signal transduction, and gene expression. The actions of polyunsaturated fatty acids have not been extensively examined in the skeletal system. Promising research on fatty acids and bone remodelling should evaluate the potential effects on pathways for osteoclastogenesis and osteoblastogenesis.

Animals↗
PubMed2000

Conjugated linoleic acid and bone biology.

Osteoporosis, osteoarthritis and inflammatory joint disease afflict millions of people worldwide. Inflammatory cytokines inhibit chondrocyte proliferation and induce cartilage degradation for which part of the response is mediated by PGE2. Excess production of PGE2 is linked to osteoporosis and arthritis and is associated with bone and proteoglycan loss. PGE2 also influences the IGF-I/IGFBP axis to facilitate bone and cartilage formation. Recent investigations with growing rats given butter fat and supplements of CLA demonstrated an increased rate of bone formation and reduced ex vivo bone PGE2 production, respectively. Furthermore, the supplements of CLA isomers resulted in their enrichment in lipids of various bone compartments of animals. The effects of CLA on bone biology in rats (IGF action and cytokines) appear to be dependent on the level of n-6 and n-3 fatty acids in the diet; however, these studies generally showed that CLA decreased ex vivo bone PGE2 production and in osteoblast-like cultures. Anti-inflammatory diets, including nutraceutical applications of CLA, may be beneficial in moderating cyclooygenase 2 (COX-2) activity or expression (influencing PGE2 biosynthesis) and might help to reduce rheumatoid arthritis (secondary osteoporosis). This review summarizes findings of CLA on bone modeling in rats and effects on cellular functions of osteoblasts and chondrocytes. These experiments indicate that CLA isomers possess anti-inflammatory activity in bone by moderating prostanoid formation.

Animals↗
PubMed2000

Dietary ratio of (n-6)/(n-3) polyunsaturated fatty acids alters the fatty acid composition of bone compartments and biomarkers of bone formation in rats.

The effects of dietary polyunsaturated fatty acids (PUFA) on ex vivo bone prostaglandin E(2) (PGE(2)) production and bone formation rate were evaluated in rats. Weanling male Sprague-Dawley rats were fed AIN-93G diet containing 70 g/kg of added fat for 42 d. The dietary lipid treatments were formulated with safflower oil and menhaden oil to provide the following ratios of (n-6)/(n-3) fatty acids: 23.8 (SMI), 9.8 (SMII), 2.6 (SMIII), and 1.2 (SMIV). Ex vivo PGE(2) production in liver homogenates and bone organ cultures (right femur and tibia) were significantly lower in rats fed diets with a lower dietary ratio of (n-6)/(n-3) fatty acids than in those fed diets with a higher dietary ratio. Regression analysis revealed a significant positive correlation between bone PGE(2) and the ratio of arachidonic acid (AA)/eicosapentaenoic acid (EPA), but significant negative correlations between bone formation rate and either the ratio of AA/EPA or PGE(2) in bone. Activities of serum alkaline phosphatase isoenzymes, including the bone-specific isoenzyme (BALP), were greater in rats fed a diet high in (n-3) or a low ratio of (n-6)/(n-3), further supporting the positive action of (n-3) fatty acids on bone formation. These results demonstrated that the dietary ratio of (n-6)/(n-3) modulates bone PGE(2) production and the activity of serum BALP in growing rats.

Animals↗
PubMed2000

Endochondral bone formation in toothless (osteopetrotic) rats: failures of chondrocyte patterning and type X collagen expression.

The pacemaker of endochondral bone growth is cell division and hypertrophy of chondrocytes. The developmental stages of chondrocytes, characterized by the expression of collagen types II and X, are arranged in arrays across the growth zone. Mutations in collagen II and X genes as well as the absence of their gene products lead to different, altered patterns of chondrocyte stages which remain aligned across the growth plate (GP). Here we analyze GP of rats bearing the mutation toothless (tl) which, apart from bone defects, develop a progressive, severe chondrodystrophy during postnatal weeks 3 to 6. Mutant GP exhibited disorganized, non-aligned chondrocytes and mineralized metaphyseal bone but without cartilage mineralization or cartilaginous extensions into the metaphysis. Expression of mRNA coding for collagen types II (Col II) and X (Col X) was examined in the tibial GP by in situ hybridization. Mutant rats at 2 weeks exhibited Col II RNA expression and some hypertrophied chondrocytes (HC) but no Col X RNA was detected. By 3rd week, HC had largely disappeared from the central part of the mutant GP and Col II RNA expression was present but weak and in 2 separate bands. Peripherally the GP contained HC but without Col X RNA expression. This abnormal pattern was exacerbated by the fourth week. Bone mineralized but cartilage in the GP did not. These data suggest that the tl mutation involves a regulatory function for chondrocyte maturation, including Col X RNA synthesis and mineralization, and that the GP abnormalities are related to the Col X deficiency. The differences in patterning in the tl rat GP compared to direct Col X mutations may be explained by compensatory effects.

Animals↗
PubMed1999

The toothless osteopetrotic rat has a normal vitamin D-binding protein-macrophage activating factor (DBP-MAF) cascade and chondrodysplasia resistant to treatments with colony stimulating factor-1 (CSF-1) and/or DBP-MAF.

The osteopetrotic rat mutation toothless (tl) is characterized by little or no bone resorption, few osteoclasts and macrophages, and chondrodysplasia at the growth plates. Short-term treatment of tl rats with colony-stimulating factor-1 (CSF-1) has been shown to increase the number of osteoclasts and macrophages, producing dramatic resolution of skeletal sclerosis at some, but not all, sites. Defects in production of vitamin D-binding protein-macrophage activating factor (DBP-MAF) have been identified in two other independent osteopetrotic mutations of the rat (op and ia), and two in the mouse (op and mi), in which macrophages and osteoclasts can be activated by the administration of exogenous DBP-MAF. The present studies were undertaken to examine the histology and residual growth defects in tl rats following longer CSF-1 treatments, to investigate the possibility that exogenous DBP-MAF might act synergistically with CSF-1 to improve the tl phenotype, and to assess the integrity of the endogenous DBP-MAF pathway in this mutation. CSF-1 treatment-with or without DBP-MAF-induced resorption of metaphyseal bone to the growth plate on the marrow side, improved slightly but did not normalize long bone growth, and caused no improvement in the abnormal histology of the growth plate. Injections of lysophosphatidylcholine (lyso-Pc) to prime macrophage activation via the DBP-MAF pathway raised superoxide production to similar levels in peritoneal macrophages from both normal and mutant animals, indicating no defect in the DBP-MAF pathway in tl rats. Interestingly, pretreatments with CSF-1 alone also increased superoxide production, although the mechanism for this remains unknown. In summary, we find that, unlike other osteopetrotic mutations investigated to date, the DBP-MAF pathway does not appear to be defective in the tl rat; that additional DBP-MAF does not augment the beneficial skeletal effects seen with CSF-1 alone; and that the growth plate chondrodystrophy seen in this mutation is unaffected by either molecule. Thus, the tl mutation intercepts the function of a gene required for both normal endochondral ossification and bone resorption, thereby uncoupling the coordination of skeletal metabolism required for normal long bone growth.

Animals↗
PubMed1999

Marked osteoblastopenia and reduced bone formation in a model of multiple myeloma bone disease in severe combined immunodeficiency mice.

We report on an in vivo model of human myeloma producing bone disease in irradiated severe combined immunodeficiency disease mice using the human myeloma cell line JJN-3 and its subline JJN-3 T1. The cell lines are not Epstein-Barr virus transformed and produce large amounts of hepatocyte growth factor (HGF). Mice had radiological signs of osteolysis and mild hypercalcemia. Xenografted cells were predominantly found in bone marrow and brown adipose tissue, but also in meninges and liver. Take was documented by histopathological examination, immunophenotyping of cultured bone marrow, and radiography. HGF was detected in serum and bone marrow plasma. Disease generally occurred within 45 days of intravenous inoculation and was signaled by paraparesis or signs of intracranial neoplasia. More than 90% of the mice had take of xenografts. The subline JJN-3 T1 gave more reproducible bone marrow take than the native cell line. Bone histomorphometric examination revealed a 99% reduction in osteoblast counts and a 33% reduction in osteoclast counts in areas of tumor growth. Bone formation rates were reduced by 53%. The results suggest that osteoblastopenia and reduced bone formation is of importance for the occurrence of osteolytic lesions in this model.

Animals↗
PubMed1999

Dietary conjugated linoleic acids alter serum IGF-I and IGF binding protein concentrations and reduce bone formation in rats fed (n-6) or (n-3) fatty acids.

A study was designed to examine the effects of dietary conjugated linoleic acid (CLA) on serum concentrations of insulin-like growth factor-I (IGF-I) and IGF binding proteins (IGFBP) and the relationship of these factors to bone metabolism. Weanling male rats were fed AIN-93G diet containing 70 g/kg of added fat for 42 days. Treatments included 0 g/kg or 10 g/kg of CLA and soybean oil (SBO) or menhaden oil + safflower oil (MSO) following a 2 x 2 factorial design. Serum IGFBP was influenced by dietary polyunsaturated fatty acid (PUFA) type ((n-6) and (n-3)) and CLA (p = 0.01 for 38-43 kDa bands corresponding to IGFBP-3). CLA increased IGFBP level in rats fed SBO (p = 0.05) but reduced it in those fed MSO (p = 0.01). Rats fed MSO had the highest serum IGFBP-3 level. Both (n-3) fatty acids and CLA lowered ex vivo prostaglandin E2 production in bone organ culture. In tibia, rats given CLA had reduced mineral apposition rate (3.69 vs. 2.79 microm/day) and bone formation rate (BFR) (0.96 vs. 0.65 microm3/microm2/day); however, the BFR tended to be higher with MSO. Dietary lipid treatments did not affect serum intact osteocalcin or bone mineral content. These results showed that dietary PUFA type and CLA modulate local factors that regulate bone metabolism.

Animals↗
PubMed1999

Skeletal resistance to 1,25-dihydroxyvitamin D3 in osteopetrotic rats.

The osteopetrotic (op/op) rat mutation is a lethal mutation in which decreased osteoclast function (bone resorption) coexists with markedly elevated serum levels of 1 ,25-dihydroxyvitamin D3[1,25(OH)2D3]. Increased circulating levels of 1,25(OH)2D3 have been reported in other osteopetrotic animal mutations and in some osteopetrotic children. This study examined the effects of 1,25(OH)2D3 infusions on serum and skeletal parameters in normal and mutant rats of op stock. We also examined vitamin D receptor expression and binding in bone cells from op normal and mutant animals. Four-week-old normal and mutant rats were infused either with propylene glycol (used as controls) or with 12.5-125 ng of 1,25(OH)2D3/d using osmotic minipumps implanted subcutaneously for 1 wk. Sera were analyzed for calcium, phosphorus, and 1,25(OH)2D3 levels. Histomorphometric analyses of proximal tibiae from treated normal (50 ng/d) and op mutant (125 ng/d) rats and their vehicle-infused controls were performed. Normal animals infused with 1,25(OH)2D3 exhibited a dose-dependent increase in serum calcium levels. Histomorphometric analyses of metaphyseal bone within the primary spongiosae region showed that 1,25(OH)2D3 increased osteoclast number with a reduction in osteoblast surface associated with a decrease in growth plate cartilage thickness. However, similar analyses on secondary spongiosae showed a decrease in osteoclast number and surface associated with an anabolic response. Op mutants infused with 1,25(OH)2D3 did not exhibit any change in serum calcium levels or histomorphometric parameters related to growth plate cartilage and metaphyseal bone compared with mutant controls. Vitamin D mRNA and protein levels were increased twoto threefold in op mutants compared to age-matched normal rats. However, binding affinity of 1,25(OH)2D3 to its receptor was similar between op mutant and normal animals. High dose calcitriol therapy, under the conditions and period of treatment used in this study, failed to stimulate bone turnover in op rats, suggesting that they are resistant to the skeletal effects of 1,25(OH)2D3. The failure of osteoclast activation in response to 1,25(OH)2D3 treatment may be associated with osteoblast incompetence in this mutation.

Animals↗
PubMed1997

Confessions of an American clinical anatomist.

The American Association of Clinical Anatomists (AACA) is a diverse group that includes practicing clinicians, some of whom work outside the academic realm, and other clinicians and basic scientists whose primary responsibility is to patient care, publication, and teaching. This essay pointedly examines why our professional activities often do not lend themselves to the personal and professional realizations for promotion, tenure, and prestige enjoyed by most research-oriented colleagues. Thus the issue of how we can thrive as a distinct group of academic professionals warrants sincere dialogue. Most of the scholarship contributed over the past 2 years to Clinical Anatomy has come from investigators outside the AACA, and only 11% of the AACA membership have published in Clinical Anatomy during this time. A self-examination and analyses of the issues that may bear on these findings are discussed in the hope that they may prompt introspection and encourage development of individual and association strategies that promote increased membership support of the AACA and its journal.

Anatomy↗
PubMed1997

Dietary lipids modulate bone prostaglandin E2 production, insulin-like growth factor-I concentration and formation rate in chicks.

This study examined the effects of dietary fat on the fatty acid composition of liver and bone, and on the concentration of insulin-like growth factor-I (IGF-I) in liver and bone, as well as the relationship of these factors to bone metabolism. Day-old male broiler chicks were given a semipurified diet containing one of four lipid sources: soybean oil (SBO), butter+corn oil (BC), margarine+corn oil (MAC), or menhaden oil+corn oil (MEC) at 70 g/kg of the diet. At 21 and 42 d of age, chicks fed MEC had the highest concentration of (n-3) fatty acids [20:5(n-3), 22:5(n-3) and 22:6(n-3)] in polar and neutral lipids of cortical bone but the lowest amount of 20:4(n-6) in polar lipids. Diets containing t-18:1 fatty acids (MAC and BC) resulted in t18:1 accumulation in bone and liver. Bone IGF-I concentration increased from 21 to 42 d in chicks given the SBO and BC diets. Tibial periosteal bone formation rate (BFR) was higher in chicks given BC compared with those consuming SBO and MEC at 21 d. The higher BFR and concentrations of hexosamine in serum and IGF-I in cartilage, but lower 20:4(n-6) content in bone polar lipids in chicks given BC compared with those given SBO suggest that BC optimized bone formation by altering the production of bone growth factors. A second study confirmed that dietary butter fat lowered ex vivo prostaglandin E2 production and increased trabecular BFR in chick tibia. These studies showed that dietary fat altered BFR perhaps by controlling the production of local regulatory factors in bone.

Animals↗
PubMed1996

Dietary (n-3) and (n-6) polyunsaturates and acetylsalicylic acid alter ex vivo PGE2 biosynthesis, tissue IGF-I levels, and bone morphometry in chicks.

This study examined the effects of dietary (n-6) and (n-3) polyunsaturated fatty acids (PUFA) and acetylsalicylic acid (ASA) on bone ash content, morphometry, fatty acid composition, ex vivo PGE2 biosynthesis, tissue IGF-I concentration, and serum alkaline phosphatase (ALPase) activity in chicks. Newly hatched chicks were fed a semipurified diet containing soybean oil (S) or menhaden oil / safflower oil (M) at 90 g/kg. At 4 days of age, chicks were divided into four equal treatment groups receiving 0 mg [symbol: see text] or 500 mg [symbol: see text] of ASA/kg of diet: S[symbol: see text]ASA, M[symbol: see text]ASA, S[symbol: see text]ASA, and M[symbol: see text]ASA. Lipid and ASA treatments did not affect bone length, bone ash, or bone mineral content in chicks. Chicks fed M had increased fractional labeled trabecular surface and tissue level bone formation rates, independent of ASA treatment, compared with those given S. A significant fat x ASA interaction effect was found for trabecular bone volume, thickness, separation, and number. Chicks fed S had higher 20:4(n-6) but lower 20:5(n-3) concentrations in liver and bone compared with those given M. Ex vivo PGE2 biosynthesis was higher in liver homogenates and bone organ cultures of chicks fed S compared with the values for those given M at 17 days. ASA treatment decreased ex vivo PGE2 production in liver homogenates and bone organ cultures of chicks, independent of the dietary lipids. Chicks fed ASA had a lower concentration of IGF-I in tibiotarsal bone compared with those not given ASA at 19 days. Serum ALPase activity was higher in chicks given M compared with those fed S, but the values were reversed with ASA feeding. This study demonstrated that both dietary fat and ASA modulated bone PGE2 biosynthesis, and that (n-3) PUFA and fat x ASA interactions altered bone morphometry.

Alkaline Phosphatase↗
PubMed1996

Abnormalities in bone cell function and endochondral ossification in the osteopetrotic toothless rat.

The toothless (tl) rat is an osteopetrotic mutation whose excess skeletal mass is produced by a defect in its skeletal microenvironment. Its skeletal sclerosis fails to be cured by bone marrow transplantation but is largely reversed by exogenous administration of colony stimulating factor 1 which increases osteoclast neogenesis and resorptive activity. Recent studies have also indicated abnormalities in growth plate cartilage morphology and in osteoblast number and function in the tl rat. The present histomorphometric study examined static and kinetic parameters of bone cell and cartilage function in young (3-5-week-old) animals of tl stock for evidence of tissue level dysfunction. Mineralization of growth plate cartilage in mutants occurred only in the lateral regions of the growth plate, not in the central region, and longitudinal bone growth was significantly reduced (36%-61%) in mutants at the ages examined. Bone volume and trabecular thickness were greater in mutants despite significant reductions in their osteoblast populations and bone formation rates (two to threefold lower). Mutants also showed progressive age- and metaphyseal site-related decreases in osteoblast numbers which, compared to normal littermates, may relate to differences in osteoprogenitor cell pools, osteoblast lifespan, or resorption-derived skeletal growth factors locally available to support and maintain normal osteoblast phenotype. Osteoclast number per millimeter bone perimeter was reduced 96-fold in mutants and showed no age- or metaphyseal site-related changes. This study presents evidence in support of defects in chondrocyte and bone cell function in the tl rat and reveals the specific tissue locations where they occur.

Analysis of Variance↗
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↗