SEARCH · PubMed Health

Results for “Lactoferrin”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources

PubMed1992

Characterization of lactoferrin binding by Aeromonas hydrophila.

Various lactoferrin preparations (iron-saturated and iron-depleted human milk lactoferrins and bovine milk and colostrum lactoferrins) were bound by Aeromonas hydrophila. Binding was (i) reversible (65% of bound lactoferrin was displaced by unlabeled lactoferrin), (ii) specific (lactoferrin but not other iron-containing glycoproteins such as ferritin, transferrin, hemoglobin, and myoglobin inhibited binding), and (iii) significantly reduced by pepsin and neuraminidase treatment of the bacteria. The glycosidic domains of the lactoferrin molecule seem to be involved in binding since precursor monosaccharides of the lactoferrin oligosaccharides (mannose, fucose, and galactose) and glycoproteins which have homologous glycosidic moieties similar to those of the lactoferrin oligosaccharides (asialofetuin or fetuin) strongly inhibited lactoferrin binding. A. hydrophila also binds transferrin, ferritin, cytochrome c, hemin, and Congo red. However, binding of these iron-containing compounds seems to involve bacterial surface components different from those required for lactoferrin binding. Expression of lactoferrin binding by A. hydrophila was influenced by culture conditions. In addition, there was an inverse relationship between lactoferrin binding and siderophore production by the bacterium.

Aeromonas hydrophila↗

PubMed1991

Origin of intact lactoferrin and its DNA-binding fragments found in the urine of human milk-fed preterm infants. Evaluation by stable isotopic enrichment.

The origin of intact (78-kD) lactoferrin found in the urine of human milk-fed preterm infants was investigated using human milk containing proteins enriched with [13C]leucine and [15N2]lysine or [2H4]lysine. Mothers of infants selected for the study were infused i.v. with [13C] leucine and [15N2]lysine or [2H4]lysine to label milk proteins. The labeled milk was collected from each mother, pooled, fortified with a lyophilized human milk fraction, and fed to her preterm infant by continuous orogastric infusion for a period of 48 h. Urine was collected from each infant for 96 h. Intact lactoferrin (78 kD) and DNA-binding lactoferrin fragments (51 and 39 kD) were purified from the urine by affinity chromatography on columns of immobilized single-stranded DNA-agarose. The concentration and isotopic enrichment of the intact lactoferrin and DNA-binding fragments were determined separately after their isolation by high-performance reverse-phase (phenyl) chromatography. Mass spectral analyses indicated that the isotopic enrichment of the purified urinary lactoferrin was 87 to 100% of that in the labeled human milk lactoferrin. Similar results were obtained for the isolated DNA-binding lactoferrin fragments. The ratios of isotopically labeled leucine to lysine in the purified milk lactoferrins and urinary lactoferrins were similar for each mother/infant pair. Isotopically labeled lysine, added to the milk as free amino acid, was not incorporated into the purified urinary lactoferrin. These results demonstrate that undegraded (78-kD) lactoferrin of maternal origin is absorbed by the gut and excreted intact in the urine of preterm infants; nearly all of the urinary lactoferrin was of maternal origin. The possible immunoregulatory functions of the absorbed intact, maternal lactoferrin are discussed.

DNA-Binding Proteins↗

PubMed1996

Growth inhibitory effects of bovine lactoferrin to Toxoplasma gondii parasites in murine somatic cells.

Lactoferrin (LF) is known to have broad spectrum antimicrobial properties. In regards to its defense mechanism against parasitic infection, it has shown phagocytic activity in the destruction of amastigotes, an intracellular parasitic form of Trypanosoma cruzi in macrophages. The effect of bovine lactoferrin on the intracellular growth Toxoplasma gondii parasites was examined in murine macrophage and embryonal cells. Co-cultures of host cells with the parasites were supplemented with either lactoferrin, apo-lactoferrin, holo-lactoferrin or transferrin in the culture media for varying periods. The growth activity of intracellular parasites in the host cells was determined by the measurement of selective incorporation of 3H-uracil. Supplement of lactoferrin had no effect on the penetration activity of the parasites, while development of intracellular parasites was inhibited linearly in concentration of lactoferrin. Supplement of apo-lactoferrin and holo-lactoferrin, but not transferrin showed similar effects. These suggest that lactoferrin induces the inhibitory effects on the development of intracellular parasites. Pretreatment of lactoferrin to the macrophages, however, did not show any inhibitory effects. Whereas, mouse embryonal cells preincubated with lactoferrin suppressed the intracellular growth. Thus, the action of lactoferrin to macrophages would be different from that of mouse embryonal cells.

Animals↗

PubMed1999

Levels of antimicrobial molecules defensin and lactoferrin are elevated in the cerebrospinal fluid of children with meningitis.

OBJECTIVE: To measure levels of defensins and lactoferrin in the cerebrospinal fluid (CSF) of children with meningitis. STUDY DESIGN. Prospective descriptive study involving children undergoing lumbar puncture during evaluation for meningitis. METHODS: CSF concentrations of defensins and lactoferrin were determined using enzyme-linked immunosorbent assays on 19 children with bacterial meningitis, 31 children with aseptic meningitis, and 32 control children found to have normal CSF during evaluation for meningitis. Pertinent clinical and laboratory data were gathered on all children. RESULTS: CSF concentrations of both defensins and lactoferrin were elevated markedly in children with bacterial and aseptic meningitis, compared with control children. No control subject had detectable levels of defensins in the CSF. Lactoferrin was undetectable in the CSF of 31 of 32 control subjects. Defensin and lactoferrin levels were significantly higher in the CSF of children with bacterial meningitis than in those with aseptic meningitis. Defensin levels in the CSF of children with bacterial meningitis ranged from 128 ng/mL to 99 430 ng/mL with a mean of 30 311 ng/mL (SD +/- 28 865) and a median of 23 042 ng/mL. Defensin levels in the CSF of children with aseptic meningitis ranged from 0 ng/mL to 1675 ng/mL with a mean of 227 ng/mL (SD +/- 433) and a median of 23 ng/mL. A significant correlation was found between defensin levels in the CSF and the total leukocyte count and the absolute neutrophil count in the CSF of children with bacterial meningitis. Lactoferrin levels in the CSF of children with bacterial meningitis ranged from 184 ng/mL to 31 412 ng/mL with a mean of 13 209 ng/mL (SD +/- 9644) and a median of 10 382 ng/mL. Lactoferrin levels in the CSF of children with aseptic meningitis ranged from 0 ng/mL to 2715 ng/mL with a mean of 1042 ng/mL (SD +/- 878) and a median of 852 ng/mL. No correlation was found between lactoferrin level in the CSF and the total leukocyte count or the absolute neutrophil count in the CSF of children with bacterial meningitis. In our study population, the sum total of CSF defensins and lactoferrin was found to be highly sensitive and specific in delineating bacterial from aseptic meningitis when compared with standard CSF studies. CONCLUSIONS: Significant elevations of defensins and lactoferrin, indicative of endogenous local antimicrobial peptide and polypeptide release, are found in the CSF of children with meningitis. We speculate that elevations in these antimicrobial molecules may reflect the intensity of the host response. Defensins seem to parallel neutrophil activation more closely than lactoferrin. Cumulative levels of CSF defensins and lactoferrin clearly distinguished bacterial meningitis from aseptic meningitis and control patients. Further investigation is warranted to determine the usefulness of measuring defensins and lactoferrin as a diagnostic tool and therapeutic monitor in the evaluation of children with meningitis.

Anti-Infective Agents↗

PubMed2005

Lactoferrin--a novel bone growth factor.

Lactoferrin is an iron-binding glycoprotein that belongs to the transferrin family. It is present in breast milk, in epithelial secretions, and in the secondary granules of neutrophils. In healthy subjects lactoferrin circulates at concentrations of 2-7 x 10(-6) g/ml. Lactoferrin is a pleiotropic factor with potent antimicrobial and immunomodulatory activities. Recently, we have shown that lactoferrin can also promote bone growth. At physiological concentrations, lactoferrin potently stimulates the proliferation and differentiation of primary osteoblasts and also acts as a survival factor inhibiting apoptosis induced by serum withdrawal. Lactoferrin also affects osteoclast formation and, in murine bone marrow culture, lactoferrin potently inhibits osteoclastogenesis. In vivo, local injection of lactoferrin above the hemicalvaria of adult mice results in substantial increases in the dynamic histomorphometric indices of bone formation and bone area. The mitogenic effect of lactoferrin in osteoblast-like cells is mediated mainly through LRP1, a member of the family of low-density lipoprotein receptor-related proteins that are primarily known as endocytic receptors. Using confocal laser scanning microscopy, we demonstrated that fluorescently labeled lactoferrin is endocytosed and can be visualized in the cytoplasm of primary osteoblastic cells. Lactoferrin also induces activation of p42/44 MAPK signaling in primary osteoblasts, but the two pathways seem to operate independently as activation of MAPK signaling, but not endocytosis, is necessary for the mitogenic effect of lactoferrin. We conclude that lactoferrin may have a physiological role in bone growth and healing, and a potential therapeutic role as an anabolic factor in osteoporosis.

Animals↗

PubMed1993

Bovine mammary lactoferrin: implications from messenger ribonucleic acid (mRNA) sequence and regulation contrary to other milk proteins.

The regulation of bovine mammary lactoferrin, an important component of the antimicrobial defenses of the mammary gland, is poorly understood compared with the other milk proteins. The complete sequence for bovine lactoferrin mRNA shows it to be highly homologous to other lactoferrins and transferrins. However, regional differences in the deduced AA sequence of bovine lactoferrin compared with human lactoferrin and transferrin imply functional differences between them. Steady-state levels of bovine lactoferrin mRNA (by Northern blot) in the bovine mammary gland indicate that bovine lactoferrin expression is minimal in the developing and lactating gland but is strongly induced by mammary involution. The overall regulation of bovine lactoferrin in the mammary gland appears to be contrary to that of the other milk proteins. Features identified in the mRNA of bovine mammary lactoferrin may contribute to the differences in regulation between lactoferrin and other bovine milk proteins and to differences in concentrations of lactoferrin in milk across species. Lactoferrin secretion by bovine mammary cells grown in vitro does not appear to be dependent on prolactin and shows regulation by substratum, serum, and cell population to be different from that for casein. In contrast to casein, efficient secretion of lactoferrin from the cell does not require detachment of collagen substratum.

Amino Acid Sequence↗

PubMed1998

Identification of lactoferrin complexes in bovine mammary secretions during mammary gland involution.

Part of the antimicrobial activity of lactoferrin resides in its ability to bind to bacteria. The complexing of lactoferrin with other proteins could alter its activity. This study identified the presence of lactoferrin complexes in mammary secretions during mammary gland involution and determined the proportion of free and complexed lactoferrin in mammary secretions. Mammary secretions were collected from Holstein cows on d 7, 14, and 21 of involution. Proteins were fractionated from defatted, filtered mammary secretions by sucrose density gradient ultracentrifugation and by gel filtration chromatography. Proteins contained in separated fractions were identified by SDS-PAGE. The presence of lactoferrin was confirmed by immunoblot analysis. Lactoferrin was present as complexed forms of high molecular mass in mammary secretions at each day of involution. The majority of lactoferrin was present in complexes of higher molecular mass rather than as monomers. A majority of lactoferrin existed in fractions of approximately 250 kDa, although peaks of lactoferrin at 150, 300, and 800 kDa were also found. The presence of lactoferrin complexes may result from interactions with casein or immunoglobulins or from the formation of lactoferrin multimers in the secretions. The interaction of lactoferrin with other proteins in mammary secretions during involution may affect the antimicrobial properties of lactoferrin.

Animals↗

PubMed2004

Elevated free tear lactoferrin levels in leprosy are associated with Type 2 reactions.

PURPOSE: To determine the association of demographics, leprosy and ocular characteristics with altered levels of lactoferrin in the tears of normal subjects and leprosy patients, and to detect the presence of antibodies to lactoferrin in these tear samples. METHOD: We collected light-stimulated tears from 298 leprosy patients and an equal number of normal subjects using the glass capillary method. Free lactoferrin levels were estimated using ELISA and the presence of antibodies to lactoferrin was detected using the immuno-blotting method. Significant associations were looked for between tear lactoferrin levels and demographic characteristics, leprosy characteristics such as type of disease, duration of disease, reactions, deformity and bacterial load, and ocular complications, using chi-square and regression analysis. RESULTS: Tear lactoferrin levels with a mean (SD) of 2.55 (2.83)mg/ml in the control group were significantly different (P<0.000) from leprosy patients with a smean (SD) of 5.66 (7.21)mg/ml. Age showed an inverse correlation with tear lactoferrin levels in controls. Increased bacterial load, grade 2 leg deformity and Type 2 reactions were significantly associated (P<0.05) with increased tear lactoferrin levels. Type 2 reactions remained significantly associated (P=0.01) on multiple regression analysis. Tear lactoferrin levels were not associated with gender, serum lactoferrin levels, Type 1 reactions, face patches, treatment status, orbicularis oculi weakness, lagophthalmos, ectropion, entropion, corneal opacity, cataract and iridocyclitis. CONCLUSION: Age is inversely related to tear lactoferrin levels in normal subjects. Free lactoferrin levels in tears are significantly higher in leprosy patients compared with normal controls. Type 2 reactions in leprosy are significantly associated with elevated tear lactoferrin levels.

Adolescent↗

PubMed1983

Suppression of mouse myelopoiesis by administration of human lactoferrin in vivo and the comparative action of human transferrin.

Purified human lactoferrin was assessed for its influence in vivo in untreated mice and in mice undergoing rebound myelopoiesis after sublethal dosages of Cytoxan. Fully iron-saturated lactoferrin suppressed the numbers of granulocytes and monocytes per femur, the numbers of granulocyte-macrophage progenitor cells (CFU-GM) per femur and spleen, and decreased the cycle status of femoral and splenic CFU-GM. These effects were detected after administration of lactoferrin i.v. or i.p. into untreated and Cytoxan-treated mice. The suppressive effects on cellularity and numbers of CFU-GM per femur were apparent to a greater degree in mice treated with Cytoxan, and the i.v. route appeared preferable to the i.p. route. Heat-treated lactoferrin, inactive in vitro, was inactive in vivo, but iron-depleted (apo-) lactoferrin, inactive in vitro, was active in vivo, suggesting that the apo-lactoferrin acquired the iron in vivo that was necessary to change it into an active form. Titration of the effects of lactoferrin in Cytoxan-treated mice demonstrated a plateau curve of suppression of nucleated cells and CFU-GM per femur with dosages ranging from 100 micrograms to 10(-4) micrograms lactoferrin per mouse, with loss of activity at 10(-5) micrograms. The suppressive effect of lactoferrin on cycle status of CFU-GM required concentrations of 10 micrograms or higher. The effects of lactoferrin were reversible with time, with the suppressive influence on cycling status being lost before that on numbers of CFU-GM per femur. Purified human transferrin was also assessed for its influence in mice undergoing rebound myelopoiesis. Transferrin decreased the nucleated cellularity and the number of CFU-GM per femur and per spleen, but had little or no influence on the cycling status of CFU-GM and differed in its temporal effect on myelopoiesis from that of lactoferrin. These results suggest that lactoferrin and transferrin suppress the number of progenitor cells moving into the CFU-GM compartment and lactoferrin suppresses the cycling status of cells within the CFU-GM compartment. These effects are probably mediated by an action on the production of factors necessary for movement of cells into, and cell cycling within, the CFU-GM compartment.

Animals↗

PubMed1994

Lactoferrin receptors in intestinal brush border membranes.

Lactoferrin from milk may have a physiological effect on the neonate by stimulating iron acquisition and/or mucosal growth. We have hypothesized that in order to achieve such an effect(s), lactoferrin will bind to a specific receptor located on the mucosal surface of the enterocyte. We have studied the presence of lactoferrin receptors in the brush border membrane from infant rhesus monkey intestine and from fetal and infant human intestine. The receptor exhibits saturation kinetics and the binding is specific for human and monkey lactoferrin--bovine lactoferrin or human transferrin do not bind to the receptor or compete with the binding of the primate lactoferrins. Enzymatic deglycosylation does not affect the binding of human lactoferrin to its receptor, suggesting that the glycan(s) is not needed for receptor recognition. Competitive binding experiments showed that holo-lactoferrin was more effective than less Fe-saturated forms of lactoferrin with regard to receptor binding. Mn-lactoferrin bound to the receptor, while we were unable to prepare Zn-lactoferrin in any physiological buffer. The human lactoferrin receptor was isolated and found to have a MW of approximately 110 kDa. This receptor has now been cloned and is being sequenced.

Animals↗

PubMed1994

Proposed mechanisms for the involvement of lactoferrin in the hydrolysis of nucleic acids.

Lactoferrin has recently been proposed to have ribonuclease activity in the absence of bound iron. We and others have demonstrated previously that lactoferrin interacts with DNA and will bind a number of transition metal ions via surface-exposed histidyl residues. In the present study, we investigated the possibility that surface-bound copper ions on lactoferrin may catalyze the production of active oxygen species responsible for the hydrolysis of nucleic acids. Purified lactoferrin (apo- and holo-forms) was incubated with CuCl2 in solution to obtain lactoferrin with surface binding sites saturated by Cu(II)ions. the lactoferrin-Cu(II) complex was purified by Bio-Gel P-6 chromatography columns and tested for hydrolytic activity against DNA and RNA as analyzed by agarose gel electrophoresis. Incubation of lactoferrin-Cu(II) complexes with supercoiled plasmid Bluescript II SK DNA led to the rapid formation of relaxed open circular or linear forms of DNA characterized by changed electrophoretic mobility. Lactoferrin with bound Cu(II) also caused extensive degradation of yeast tRNA molecules in the presence of hydrogen peroxide. Covalent modification of surface-exposed histidyl residues by carboxyethylation with diethylpyrocarbonate abolished the lactoferrin-associated hydrolytic activity. These results indicate that lactoferrin-bound Cu(II) can indeed facilitate the hydrolysis of DNA and RNA molecules. Copper-binding sites on lactoferrin appear to serve as centers for repeated production of hydroxyl radicals via a Fenton-type Haber-Weiss reaction. Enhanced nuclease activity associated with elevated local concentrations of lactoferrin would promote microbial degradation.

Apoproteins↗

PubMed1998

Prevalence and clinical significance of anti-lactoferrin autoantibodies in inflammatory bowel diseases and primary sclerosing cholangitis.

Anti-neutrophil cytoplasmic antibodies (ANCA) are autoantibodies directed against cytoplasmic constituents of neutrophil granulocytes. Antibodies with specificity for proteinase 3 and myeloperoxidase are seromarkers for systemic vasculitides. ANCA with specificity for lactoferrin were described in patients with several idiopathic inflammatory diseases, such as the inflammatory bowel diseases and rheumatoid arthritis. However, the clinical significance of anti-lactoferrin autoantibodies is still unclear. In this study, we determined the clinical significance of anti-lactoferrin autoantibodies in sera from large groups of patients with ulcerative colitis (UC), Crohn's disease (CD), and primary sclerosing cholangitis (PSC). Antibodies to human lactoferrin were detected by ELISA and by immunoblotting, using an extract of sonicated neutrophils as antigen source. Autoantibodies to lactoferrin were found in 29% of patients with UC, 13% of patients with CD, and 22% of patients with PSC. In inflammatory bowel diseases, the presence of anti-lactoferrin antibodies was not related to treatment, disease activity, duration of disease, or disease extent. In PSC, the presence of autoantibodies to lactoferrin did not correlate with duration of disease or the presence of cirrhosis. However, patients with PSC and coexistent UC had significantly more frequently antibodies to lactoferrin than PSC patients without IBD. In conclusion, autoantibodies to lactoferrin are a common feature of inflammatory bowel diseases and PSC. However, the clinical significance of those autoantibodies is limited as they lack sensitivity and specificity for those disorders. Future research should address the pathophysiological role of anti-lactoferrin ANCA and the influence of anti-lactoferrin ANCA binding on the functional properties of the lactoferrin molecule.

Autoantibodies↗

PubMed1993

Effect of bovine milk antigens and egg lysozyme on the binding of 59Fe-lactoferrin to platelet plasma membranes.

1. Platelets bind specifically to lactoferrin. A significant similarity between human lactoferrin and some bovine milk proteins has been established. 2. Because of the structural homology of lactoferrin and cows milk proteins they are able to influence lactoferrins regulatory function on the level of its binding to membrane receptors on platelets. 3. An inhibitory effect of bovine alpha-lactalbumin and of beta-lactoglobulin on lactoferrin-receptor interaction was shown. 4. Bovine alpha-lactalbumin competes with lactoferrin for the binding sites. 5. Scatchard plot analysis of data shows one binding site for lactoferrin in the presence of alpha-lactalbumin with an affinity constant, Ka = 0.46 x 10(9) mol/l and 335 receptors/cell. 6. The inhibitory effect of beta-lactoglobulin reaches 62% and is different for the common fraction beta-lactoglobulin and the genetic variants beta-lactoglobulin A and B. 7. beta-lactoglobulin does not compete with lactoferrin for the membrane receptors. 8. Bovine casein and egg lysozyme stimulate 59Fe-lactoferrin binding to the receptors. The mechanism of these effects is still unknown. 9. Tested alimentary antigens are able to interact with lactoferrin and also with some platelet membrane structures. 10. Established changes in lactoferrin binding to the platelet membrane might be in relation to lactoferrins regulatory function and (or) eliminating mechanisms of these alimentary antigens.

Animals↗

PubMed1984

Iron uptake and increased intracellular enzyme activity follow host lactoferrin binding by Trichomonas vaginalis receptors.

Lactoferrin acquisition and iron uptake by pathogenic Trichomonas vaginalis was examined. Saturation binding kinetics were obtained for trichomonads using increasing amounts of radioiodinated lactoferrin, while no significant binding by transferrin under similar conditions was achieved. Only unlabeled lactoferrin successfully and stoichiometrically competed with 125I-labeled lactoferrin binding. Time course studies showed maximal lactoferrin binding by 30 min at 37 degrees C. Data suggest no internalization of bound lactoferrin. The accumulation of radioactivity in supernatants after incubation of T. vaginalis with 125I-labeled lactoferrin and washing in PBS suggested the presence of low affinity sites for this host macromolecule. Scatchard analysis indicated the presence of 90,000 receptors per trichomonad with an apparent Kd of 1.0 microM. Two trichomonad lactoferrin binding proteins were identified by affinity chromatography and immunoprecipitation of receptor-ligand complexes. A 30-fold accumulation of iron was achieved using 59Fe-lactoferrin when compared to the steady state concentration of bound lactoferrin. The activity of pyruvate/ferrodoxin oxidoreductase, an enzyme involved in trichomonal energy metabolism, increased more than sixfold following exposure of the parasites to lactoferrin, demonstrating a biologic response to the receptor-mediated binding of lactoferrin. These data suggest that T. vaginalis possesses specific receptors for biologically relevant host proteins and that these receptors contribute to the metabolic processes of the parasites.

Animals↗

PubMed2003

Expression, characterization, and biologic activity of recombinant human lactoferrin in rice.

BACKGROUND: Lactoferrin has been suggested to have many biologic activities, such as facilitating iron absorption and having antimicrobial and antiinflammatory effects. In humans, several of these activities are likely to only be facilitated by human lactoferrin because they depend on the binding of human lactoferrin to specific receptors. Rice may be a useful vehicle to introduce recombinant human lactoferrin to infant foods because it has low allergenicity and is likely to be safer than using microorganisms or transgenic animals. METHODS: Recombinant human lactoferrin was expressed in the rice cell culture system, and its biologic activity was assessed by iron-binding and -releasing properties, antimicrobial activity, and binding and uptake to Caco-2 cells. The authors also compared the stability of recombinant and native human lactoferrins against heat, low pH, and in vitro digestion. RESULTS: Biologic activity of rice-expressed recombinant human lactoferrin was similar to that of native human lactoferrin. Heat-treated proteins retained their functional activities except with severe treatment at 100 degrees C for 8 seconds, which disturbed the iron-binding capacity of recombinant human lactoferrin. Both types of proteins retained their functional activities between pH 2 and 7.4. After in vitro digestion, 50% of both proteins were detectable by enzyme linked immunosorbent assay. The remaining native and recombinant lactoferrins retained antimicrobial and Caco-2 binding and uptake activities. CONCLUSIONS: The results indicate recombinant human lactoferrin has stability similar to native human lactoferrin when exposed to thermal treatment, pH treatment, and in vitro digestion, suggesting it may be active when added to infant formula.

Amino Acid Sequence↗

PubMed2006

Lactoferrin and bone; structure-activity relationships.

The maintenance of the mechanical integrity of the skeleton depends on bone remodeling, the well-coordinated balance between bone formation by osteoblasts and bone resorption by osteoclasts. The coupled action of osteoblasts and osteoclasts is regulated by the action of many local and circulating hormones and factors as well as central regulation by a neurological mechanism. We have previously shown that lactoferrin can promote bone growth. At physiological concentrations, lactoferrin potently stimulates the proliferation and differentiation of primary osteoblasts and acts as a survival factor. Lactoferrin also affects osteoclasts, potently inhibiting their formation. In vivo, local injection of lactoferrin results in substantial increases in bone formation and bone area. In a critical bone-defect model in vivo, lactoferrin was also seen to promote bone growth. The mitogenic effect of lactoferrin in osteoblast-like cells is mediated mainly through low-density lipoprotein-receptor protein-1 (LRP1), a member of the low-density lipoprotein-receptor-related proteins that are primarily known as endocytic receptors; however, LRP1 is not necessary for the anti-apoptotic actions of lactoferrin. Lactoferrin also induces the activation of p42/44 mitogen-activated protein kinase (MAPK) signalling and the PI3-kinase-dependent phosphorylation of Akt in osteoblasts. In this study, we examined other properties of lactoferrin and the way they affect osteogenic activity. The degree of glycosylation, iron-binding, and the structure-activity relationships indicate that lactoferrin maintains osteogenic activity in deglycosylated, holo, and apo forms, and in with various small fragments of the molecule. These data suggest that lactoferrin signals through more than 1 membrane-bound receptor to produce its anabolic skeletal effects, and that it signals through diverse pathways. We conclude that lactoferrin might have a physiological role in bone growth and healing and a potential therapeutic role as an anabolic factor in osteoporosis.

Amino Acid Sequence↗

PubMed2004

The low-density lipoprotein receptor-related protein 1 is a mitogenic receptor for lactoferrin in osteoblastic cells.

Lactoferrin induces osteoblast proliferation and survival in vitro and is anabolic to bone in vivo. The molecular mechanisms by which lactoferrin exerts these biological actions are not known, but lactoferrin is known to bind to two members of the low-density lipoprotein receptor family, low- density lipoprotein receptor-related proteins 1 (LRP1) and 2 (LRP2). We have examined the role(s) of these receptors in the actions of lactoferrin on osteoblasts. We show that lactoferrin binds to cultured osteoblastic cells, and that LRP1 and LRP2 are expressed in several osteoblastic cell types. In primary rat osteoblastic cells, the LRP1/2 inhibitor receptor associated protein blocks endocytosis of lactoferrin and abrogates lactoferrin-induced p42/44 MAPK signaling and mitogenesis. Lactoferrin-induced mitogenesis is also inhibited by an antibody to LRP1. Lactoferrin also induces receptor associated protein-sensitive activation of p42/44 MAPK signaling and proliferation in osteoblastic human SaOS-2 cells, which express LRP1 but not LRP2. The mitogenic response of LRP1-null fibroblastic cells to lactoferrin is substantially reduced compared with that of cells expressing wild-type LRP1. The endocytic and signaling functions of LRP1 are independent of each other, because lactoferrin can activate mitogenic signaling in conditions in which endocytosis is inhibited. Taken together, these results 1) suggest that mitogenic signaling through LRP1 to p42/44 MAPKs contributes to the anabolic skeletal actions of lactoferrin; 2) demonstrate growth-promoting actions of a third LRP family member in osteoblasts; and 3) provide further evidence that LRP1 functions as a signaling receptor in addition to its recognized role in ligand endocytosis.

Animals↗

PubMedDate not supplied

Serum lactoferrin and immunoglobulin G concentrations in healthy or ill neonatal foals and healthy adult horses.

BACKGROUND: Lactoferrin is a colostral glycoprotein with antimicrobial properties. HYPOTHESES: (1) Serum lactoferrin and immunoglobulin G (IgG) concentrations are correlated and increase in healthy foals after ingestion of colostrum; (2) compared to healthy foals, ill foals will have lower lactoferrin concentrations that correlate with their IgG concentration, neutrophil count, the diagnosis of sepsis, and survival; and (3) plasma concentrations of lactoferrin will be less than serum concentrations. ANIMALS: Healthy foals (n = 16), mature horses (n = 10), and ill foals 1-4 days old (n = 111) that were examined for suspected sepsis were used for blood collection. Colostrum was obtained from 10 healthy mares unrelated to the foals. METHODS: Blood was obtained from the healthy foals at birth and 1-3 days of age and from the ill foals at admission. Serum IgG was quantified by single radial immunodiffusion (SRID). Lactoferrin concentrations in colostrum and blood were determined by an enzyme-linked immunosorbant assay. The sepsis score, blood culture results, neutrophil counts, and survival were obtained on ill foals. RESULTS: The mean colostral lactoferrin concentration was 21.7 microg/mL. Compared to values at birth, serum IgG (18+/-2 versus 2,921+/-245 mg/dL, SEM) and lactoferrin (249+/-39 versus 445+/-63 ng/mL, SEM) concentrations were significantly greater in healthy foals 1-3 days old. Serum lactoferrin concentration in 1-3-day-old healthy foals was not different from mature horses or ill foals. IgG and lactoferrin concentrations were significantly correlated only in healthy foals. Serum lactoferrin concentrations were significantly lower in ill neutropenic foals. The serum IgG concentration was significantly lower in ill foals as compared to healthy foals. Only serum IgG was significantly less in ill foals with a positive sepsis score and in nonsurvivors, Plasma lactoferrin concentrations were lower than serum concentrations, although values were significantly correlated. CLINICAL IMPORTANCE: Although both serum IgG and lactoferrin concentrations increase in healthy foals after ingestion of colostrum, only serum IgG is significantly correlated with the sepsis score and outcome.

Aging↗