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PubMed1995

The potential role of the macrophage colony-stimulating factor, CSF-1, in inflammatory responses: characterization of macrophage cytokine gene expression.

In this report we report that recombinant human monocyte-macrophage colony-stimulating factor-1 (CSF-1) induces resident murine peritoneal cells (PCs) to transcribe several inflammatory cytokine genes, including interleukin (IL)-1 alpha, IL-1 beta, IL-6, and granulocyte-macrophage CSF in a dose-dependent and time-related manner. Peak mRNA levels were seen between 4 and 6 h. CSF-1 did not modulate the expression of tumor necrosis factor-alpha mRNA. The serum content of the culture medium appeared to regulate both the extent of CSF-1-induced gene transcription and the adherence properties of the cells. Decreasing the serum concentration significantly reduced CSF-1-induced transcription and was associated with the rapid spreading of the majority of the adherent cells. This reduced sensitivity to CSF-1 was paralleled by a markedly lower levels of c-fms mRNA encoding the CSF-1 receptor. Induced gene transcription was followed by the release of large quantities of IL-6 only. IL-1 activity remained associated with the cells. Neither supernatant nor cell lysate granulocyte-macrophage CSF activity was inducible above the low levels associated with control cultures. Evidence that the mononuclear phagocytes, as opposed to B or T cells, were the targets of CSF-1 was obtained in two ways: (1) PCs from B6 scid/scid and NOD scid/scid mice consisting of 78-86% MAC-1+, F4/80+ cells and few B or T cells, as shown by flow cytometry analysis, released 5- to 10-fold more IL-6 in response to CSF-1 stimulation than B6 PCs, which contained approximately 30% double-positive cells, and (2) pretreatment of B6 PCs with antibodies to the CSF-1 receptor blocked the CSF-1-induced secretion of IL-6. These data suggest that CSF-1 primes noninflammatory mononuclear phagocytes for a role in inflammatory responses but does not provide the necessary signals for either secretion or translation of all cytokines equally.

Animals↗
PubMed1996

The effect of granulocyte-macrophage colony stimulating factor (rGM-CSF) on macrophage function in microbial disease.

The haematopoietic growth factor, GM-CSF, has well-documented stimulatory effects on monocyte and macrophage functions. These effects include enhanced proliferation on their progenitor cells, increased endocytosis and metabolism of mature cells, increased function as antigen-presenting cells, and increased inhibition or killing of intracellular fungi, bacteria, protozoa and viruses. The major effect of GM-CSF on monocytes and macrophages is to enhance phagocytic and metabolic functions, including increased synthesis of molecules toxic to microbes, and to release other proinflammatory cytokines. This results in inhibition and/or killing of Candida albicans, Aspergillus, Cryptococcus, Pneumocystis, Leishmania, Mycobacteria, as well as other intracellular pathogens. GM-CSF also enhances the intracellular effectiveness of antiviral and antibacterial drugs. Viral replication may be increased in activated cells, therefore, when GM-CSF is used, a combination with appropriate antiviral drugs is recommended. Several reports in patients of successful management of microbial diseases which depend on macrophage function are now reviewed. These reports support the clinical value of GM-CSF in the management of patients with cancer and chemotherapy related monocyte/macrophage dysfunction and presumed or documented microbial disease.

Animals↗
PubMed1995

In vivo and in vitro effects of macrophage colony-stimulating factor (M-CSF) on bronchoalveolar macrophages for antihistoplasmal activity.

The in vivo and in vitro effects of M-CSF on bronchoalveolar macrophages (BAM) activity against the intracellular fungal pathogen Histoplasma capsulatum (Hc) were studied. Three days after a single subcutaneous (s.c.) dose of M-CSF (2.5 mg/kg), enhanced ex vivo antifungal activity of BAM was measured. BAM from M-CSF-treated CD-1 mice significantly (P < 0.01) inhibited the intracellular multiplication of Hc yeast cells in 20 h assays compared to BAM from control mice. This effect was not observed at days 1, 7, 11 or 21 post-treatment. A dose of 5 mg/kg s.c., but not 1 mg/kg, induced similar antifungal activity in BAM by day 3. Peritoneal macrophages (PM) from M-CSF-treated mice did not have enhanced antifungal activity at days and doses tested. BAM could also be activated for antihistoplasmal activity by M-CSF in vitro. M-CSF at 10,000 U/ml for 24 h or 5000 U/ml for 48 h induced significant (P < 0.01) inhibition of intracellular multiplication of Hc. Interferon-gamma (IFN) plus lipopolysaccharide (LPS) activated BAM and PM in vitro to inhibit intracellular multiplication of Hc (P < 0.001); the antihistoplasmal activity was completely inhibited by NG-monomethyl L-arginine (N-MMA), indicating that an L-arginine-dependent nitric oxide-producing mechanism was operative. N-MMA could not inhibit the antihistoplasmal activity of BAM or PM activated by M-CSF in vitro. The mechanism by which M-CSF-activated macrophages inhibit intracellular multiplication of Hc remains to be determined.

Animals↗
PubMedDate not supplied

Activation of mouse macrophages by muramyl dipeptide coupled with an anti-macrophage monoclonal antibody.

A rat IgG2a monoclonal antibody (mAb3A33) directed against the mouse Mac-1 antigen was conjugated with muramyl dipeptide (MDP) by using an intermediate polymer; under such conditions 75 MDP molecules were bound to one antibody molecule. A poly(L-lysine) polymer substituted with muramyl dipeptide and 3-(2-pyridyldithio)propionyl residues were prepared, the remaining lysine epsilon-amino groups were acylated with D-gluconolactone, leading to a neutral polymer; then a few polymer conjugates were coupled to mAb3A33 via a disulfide bridge. The binding capacity of the monoclonal antibody was preserved after conjugation with MDP-polymer molecules. Mouse peritoneal macrophages, incubated for 24 h with MDP-mAb3A33 conjugate became cytostatic against P815 mastocytoma cells, whereas unconjugated mAb3A33 and MDP-bound to a nonspecific rat IgG2a were ineffective. An enhancement of the cytostatic activity induced by MDP-mAb3A33 conjugate was obtained in the presence of gamma-IFN. These results show that several tens of MDP molecules can be linked to a macrophage-specific monoclonal antibody by using a neutral intermediate polymer without impairing the binding antibody capacity and that this type of MDP conjugate can efficiently activate macrophages and therefore could be the basis of the development of new antitumor therapy.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

Evidence for differential activation of arachidonic acid metabolism in formylpeptide- and macrophage-activation-factor-stimulated guinea-pig macrophages.

Alterations of phospholipid and arachidonic acid metabolism were studied by treatment of guinea-pig peritoneal-exudate macrophages with chemotactic peptide, formylmethionyl-leucylphenylalanine (fMet-Leu-Phe) and macrophage activation factor (MAF). The chemotactic peptide caused a rapid rearrangement in inositol phospholipids, including a breakdown of polyphosphoinositides within 30s, followed by a resultant formation of phosphatidylinositol (PI), diacylglycerol, phosphatidic acid and non-esterified arachidonic acid within 5 min. In addition to these sequential alterations, arachidonic acid was released mainly from PI. On the other hand, MAF induced a slow liberation of arachidonic acid, mainly from phosphatidylethanolamine (PE) and phosphatidylcholine (PC) by phospholipase A2 after the incubation period of 30 min, but not any rapid changes in phospholipids. Treatment of macrophages for 15 min with fMet-Leu-Phe produced the leukotrienes (LTs) B4, C4 and D4, prostaglandins (PG) E2 and F2 alpha and thromboxane (TX) B2. In contrast, MAF could not stimulate the production of arachidonic acid metabolites during the incubation period of 15 min, but could enhance that of PGE2, PGF2 alpha, TXB2 and hydroxyeicosatetraenoic acids at 6 h. However, the stimulated formation of LTs was not detected at any time. These results indicate that the effects of fMet-Leu-Phe on both phospholipid and arachidonic acid metabolism are very different from those mediated by MAF.

Animals↗
PubMed1990

Granulocyte-macrophage colony-stimulating factor can stimulate macrophage proliferation via persistent activation of Na+/H+ antiport. Evidence for two distinct roles for Na+/H+ antiport activation.

Macrophages respond to a variety of extracellular stimuli which can modulate the proliferation, development, activation and functional activity of these cells. The effects of two such agents, granulocytemacrophage colony-stimulating factor (GM-CSF, which stimulates proliferation) and platelet-activating factor (PAF, which stimulates chemotaxis and bactericidal activity), on cellular signal transduction mechanisms were compared. PAF can stimulate inositol lipid hydrolysis leading to Ca2+ mobilization. GM-CSF on the other hand has no effect on these events. Both agonists do, however, share an ability to activate an amiloride-sensitive Na+/H+ antiport and, furthermore, amiloride analogues are shown to inhibit the proliferative effects of GM-CSF on these cells. Long-term incubations with either PAF or GM-CSF demonstrate that it is only those cells pretreated with the latter which show a persistent activation of the antiport together with a sustained increase in intracellular pH. PAF-treated cells exhibit only a transitory increase in antiport activity, their intracellular pH levels returning to resting levels in spite of the continuous presence of the agonist in the medium. These effects of GM-CSF and PAF on Na+/H+ exchange are observed in both bicarbonate-free and bicarbonate-containing medium. These results lead us to suggest that the Na+/H+ antiport has a role in macrophage proliferation and in the regulation of intracellular pH during the oxidative burst stimulated by PAF and other agonists, and that differential mechanisms whereby this antiport is regulated exist in macrophages.

Animals↗
PubMed2000

Exacerbation of acute inflammatory arthritis by the colony-stimulating factors CSF-1 and granulocyte macrophage (GM)-CSF: evidence of macrophage infiltration and local proliferation.

CSF-1 and GM-CSF have been implicated in the pathogenesis of rheumatoid arthritis. We report the effects of CSF-1 and GM-CSF in the development of an acute methylated bovine serum albumin (mBSA)-induced murine arthritis model. Examination of histopathological features revealed that the systemic administration of CSF-1 or GM-CSF following mBSA administration into the knee resulted in the exacerbation of arthritis. This included synovial hyperplasia and joint inflammation, most evident at 7 and 14 days post-mBSA administration, and the appearance of erosive pannus tissue. The exacerbation by CSF-1 and GM-CSF was not sustained but declined in incidence and severity by 21 days post-mBSA administration, similar to the effects of IL-1beta in this model, reported here and previously. Macrophages expressing Mac-2 and F4/80 were a prominent feature of the pathology observed, particularly the infiltration of Mac-2+ macrophages seen in all mice administered CSF-1, GM-CSF or IL-1beta. Present in inflamed knees was a locally dividing population of cells which included Mac-2+ and F4/80+ macrophages. These studies demonstrate that CSF-1 and GM-CSF can exacerbate and prolong the histopathology of acute inflammatory arthritis and lend support to monocytes/macrophages being a driving influence in the pathogenesis of inflammatory arthritis.

Acute Disease↗
PubMed1999

Regulation of major histocompatibility complex class II antigens on human alveolar macrophages by granulocyte-macrophage colony-stimulating factor in the presence of glucocorticoids.

Alveolar macrophages (AM) present antigen poorly to CD4+ T cells and respond weakly to interferon-gamma (IFN-gamma) for up-regulation of major histocompatibility complex (MHC) class II and costimulatory molecule expression. In atopic asthma, however, AM exhibit enhanced antigen-presenting cell (APC) activity. Since granulocyte-macrophage colony-stimulating factor (GM-CSF) is increased in the airways of asthmatic patients, we have investigated its role in modulating the APC function of AM. The effects of glucocorticoids were also studied since earlier studies showed optimal induction of MHC antigens on monocytes by GM-CSF in their presence. GM-CSF in the presence, but not the absence, of dexamethasone enhanced the expression of HLA-DR, -DP and -DQ antigens by AM. However AM and monocytes differed in the optimal concentration of steroid required to mediate this effect (10-10 m and 10-7 m, respectively). Induction of MHC antigens was glucocorticoid specific and independent of IFN-gamma. These studies suggest the existence of an IFN-gamma-independent pathway of macrophage activation, which may be important in regulating APC function within the lung.

Adult↗
PubMed1983

Lysis of inducer T cell clones by activated macrophages and macrophage-like cell lines.

We describe a sequence of reciprocal interactions between cloned inducer T cells and antigen-presenting cells (APC) that results in selective depletion of the antigen-reactive inducer cells. We show that corecognition of antigen and I-A by hapten-reactive inducer T cell clones results in (a) release of macrophage-activating factor (MAF) and other lymphokines, (b) expression of lytic activity by a subset of MAF-sensitized APC after triggering, and (3) lysis (mediated by the activated and triggered macrophage) of the inducer T cell clone and other cells in the vicinity. We suggest that this sequence of steps may limit the extent of macrophage-mediated tissue destruction by depleting the specific inducer T cell clones that initiate the response.

Animals↗
PubMed2003

Regulation by granulocyte-macrophage colony-stimulating factor and/or steroids given in vivo of proinflammatory cytokine and chemokine production by bronchoalveolar macrophages in response to Aspergillus conidia.

Production of the proinflammatory cytokines interleukin (IL)-1 alpha and tumor necrosis factor (TNF)-alpha and of the chemotactic chemokine macrophage inflammatory protein (MIP)-1 alpha by bronchoalveolar macrophages (BAMs) from mice in response to Aspergillus conidia was tested after in vivo administration of saline, dexamethasone, cortisone acetate, granulocyte-macrophage colony-stimulating factor (GM-CSF), or a combination. Dexamethasone suppressed production of IL-1 alpha, TNF-alpha, and MIP-1 alpha; GM-CSF reduced secretion slightly but antagonized dexamethasone suppression when the two were given in combination. Cortisone acetate gave results similar to dexamethasone, but cortisone acetate suppression of BAM responses lasted 7 days, > or = 4 days longer than dexamethasone suppression. The effect of GM-CSF on cortisone acetate suppression lasted at least 7 days. GM-CSF could promote resistance to conidia by maintaining proinflammatory responses.

Animals↗
PubMed1994

Potent cholesterol-lowering effect by human granulocyte-macrophage colony-stimulating factor in rabbits. Possible implications of enhancement of macrophage functions and an increase in mRNA for VLDL receptor.

The mechanism by which granulocyte-macrophage colony-stimulating factor (GM-CSF) lowers plasma cholesterol levels is not well understood. We tested recombinant human GM-CSF (rhGM-CSF) on plasma cholesterol and triglycerides in rabbits and attempted to determine the mechanisms of the cholesterol-lowering effect. rhGM-CSF (20 micrograms.kg-1.d-1) was administered to normal and cholesterol-fed rabbits for 2 weeks and to Watanabe heritable hyperlipidemic (WHHL) rabbits for 1 week. The administration of rhGM-CSF markedly lowered cholesterol and triglycerides, an effect that persisted in normal and cholesterol-fed rabbits even after termination of treatment. The cholesterol-lowering effect of rhGM-CSF was also observed in WHHL rabbits. rhGM-CSF was capable of stimulating granulocyte-macrophage colony formation in vitro in rabbits with an effect comparable to that in humans. Northern blot analysis with rabbit very-low-density-lipoprotein (VLDL) receptor cDNA revealed that rhGM-CSF increased the levels of VLDL receptor mRNA in muscle of rabbits after only 1.5 hours of treatment compared with control (2.6-fold), with the 1.5-fold increase following a 5-day administration. No changes in the levels of LDL receptor mRNA in liver, spleen, and bone marrow were observed in the treated rabbits. These findings suggest that the cholesterol-lowering effect of rhGM-CSF may be mediated by enhancement of macrophage functions in lipid metabolism and the increase in mRNA for VLDL receptor in rabbits.

Animals↗
PubMed2001

TNF-alpha-converting enzyme cleaves the macrophage colony-stimulating factor receptor in macrophages undergoing activation.

We previously reported that macrophage activators such as LPS, IL-2, and IL-4 down-modulate the M-CSFR via a mechanism involving protein kinase C and phospholipase C. In this study, we showed that M-CSFR is shed from macrophage surface and identified the protease responsible for M-CSFR cleavage and down-modulation. The shedding of M-CSFR elicited by phorbol esters (tetradecanoylphorbol myristate acetate (TPA)) or LPS in murine BAC.1-2F5 macrophages was prevented by cation chelators, as well as hydroxamate-based competitive inhibitors of metalloproteases. We found that the protease cleaving M-CSFR is a transmembrane enzyme and that its expression is controlled by furin-like serine endoproteases, which selectively process transmembrane metalloproteases. M-CSFR down-modulation was inhibited by treating cells in vivo, before TPA stimulation, with an Ab raised against the extracellular, catalytic domain of proTNF-converting enzyme (TACE). TACE expression was confirmed in BAC.1-2F5 cells and found inhibited after blocking furin-dependent processing. Using TACE-negative murine Dexter-ras-myc cell monocytes, we found that in these cells TPA is unable to down-modulate M-CSFR expression. These data indicated that TACE is required for the TPA-induced M-CSFR cleavage. The possibility that the cleavage is indirectly driven by TACE via the release of TNF was excluded by treating cells in vivo with anti-TNF Ab. Thus, we concluded that TACE is the protease responsible for M-CSFR shedding and down-modulation in mononuclear phagocytes undergoing activation. The possible physiological relevance of this mechanism is discussed.

ADAM Proteins↗
PubMed2000

Regulation of urokinase plasminogen activator gene transcription in the RAW264 murine macrophage cell line by macrophage colony-stimulating factor (CSF-1) is dependent upon the level of cell-surface receptor.

Macrophage colony-stimulating factor (CSF-1) binds to a receptor (CSF-1R) encoded by the c-fms proto-oncogene and activates transcription of the urokinase plasminogen activator (uPA) gene in murine bone-marrow-derived macrophages. This article demonstrates that the murine macrophage cell line RAW264 responds to CSF-1 with inducible phosphorylation of cytoplasmic proteins on tyrosine residues but fails to induce transcription of uPA. The defect was correlated with a selective failure to maintain CSF-1Rs on the cell surface, whereas all RAW264 cells contained abundant CSF-1Rs within the presumptive Golgi/endoplasmic reticulum compartment. Transfection with a CSF-1R expression plasmid permitted CSF-1-dependent activation of the signalling pathway targeting an Ets/AP1 (activator protein 1) element in the uPA promoter that has been shown previously to be a target of oncogenic ras and protein kinase C pathways. Mutation of the expressed CSF-1R at either Y807 or Y559, sites of receptor tyrosine phosphorylation implicated in signal transduction, reduced but did not abolish uPA promoter activation by CSF-1. Activation by mutant CSF-1R plasmids was additive; there was no evidence of mutual complementation. The results indicate that maintenance of elevated uPA transcription by CSF-1 requires new receptors emerging continuously on the cell surface. Parallel, partly redundant, signalling pathways arising from phosphorylated tyrosines on the CSF-1R activate multiple cis-acting elements on the complex uPA promoter.

Amino Acid Substitution↗
PubMed1988

Granulocyte-macrophage colony-stimulating factor activates macrophages derived from bone marrow cultures to synthesis of MHC class II molecules and to augmented antigen presentation function.

The effects of granulocyte-macrophage (GM)-CSF on the synthesis of MHC class II molecules and on the Ag presentation capacity by bone marrow derived macrophages (BMM phi) was investigated. BMM phi obtained by in vitro culture in the presence of macrophage-CSF were negative for synthesis of I-A molecules and induced the Ag-mediated proliferation of insulin-specific T clone cells with lower efficiency than splenic accessory cells. After pulse treatment with GM-CSF for 24 to 48 h, day 12 BMM phi exhibited highly efficient Ag presentation function which was superior to that induced by IFN-gamma. Expression of membrane-bound IL-1 was augmented significantly by GM-CSF, but not by IFN-gamma. However, the T cell clone used to probe for accessory cell function of BMM phi was not dependent on IL-1 for optimal proliferation. Concomitantly, GM-CSF induced the de novo synthesis of I-A molecules, although to a lesser extent than optimal doses of IFN-gamma. Thus GM-CSF appears to elicit properties in addition to Ia molecule synthesis and membrane IL-1 expression in BMM phi being essential for efficient accessory cell function to the T clone cells. The activation of BMM phi by GM-CSF was reversible and could be repeated. These data show that GM-CSF exerts a modulatory influence on preformed BMM phi, reversibly activating cells to Ia biosynthetic potential and pronounced accessory cell capacity, thus rendering the explanation unlikely that differentiation of precursor cells into a constitutively functional state had occurred.

Adjuvants, Immunologic↗
PubMed1996

Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of CSF-1-dependent macrophages in formation of tumor stroma.

Macrophages have been suggested to play a major role in the immune response to cancer. They have also been suggested to stimulate the formation of tumor stroma and to promote tumor vascularization. The availability of the op/op mouse, which has no endogenous colony-stimulating factor 1 (CSF-1) and which possesses a profound macrophage deficiency, provides a new model to verify these notions. Subcutaneous growth of transplantable Lewis lung cancer (LLC) is markedly impaired in the op/op mice compared with normal littermates. Treatment of tumor-bearing op/op mice with human recombinant CSF-1 corrects this impairment. Histological analysis of tumors grown in op/op and normal mice revealed marked differences. Tumors grown in op/op mice display a decreased mitotic index and pronounced necrosis, particularly hemorrhagic. Moreover, particularly in the op/op tumors, peculiar sinusoid-like abortive vessels (not filled with blood) have been observed. These tumors, in contrast to tumors grown in normal mice, are almost deprived of regular arteries and veins. In contrast to tumors grown in normal mice, they exhibit almost no Sirius red-stained collagenous fibers and Gomori silver-stained reticular fibers. Our data suggest that the CSF-1-dependent macrophage subpopulation missing in op/op mice plays a primary role in supporting tumor stroma formation and tumor vascularization in murine LLC tumors.

Animals↗
PubMed2002

TNFalpha-induced macrophage chemokine secretion is more dependent on NF-kappaB expression than lipopolysaccharides-induced macrophage chemokine secretion.

The transcription factor NF-kappaB is a pivotal intracellular regulator of many inflammatory responses and it has been proposed that it represents a potential therapeutic target. As chemokines are important for the progress of an inflammatory response by the recruitment of immuno-competent cells, the role NF-kappaB plays in TNFalpha- or lipopolysaccharides (LPS)-induced chemokine secretion by human monocyte-derived macrophages was examined. Secretion of the CXC chemokines IL-8, GROalpha and ENA-78, induced by TNFalpha, was significantly suppressed by inhibiting NF-kappaB, using overexpression of IkappaBalpha. However, when induced by LPS the expression of these chemokines was unaffected. In contrast, expression of the CC chemokines MIP-1alpha, MCP-1 and RANTES inducedby TNFalpha or LPS was significantly inhibited by the overexpression of IkappaBalpha. Therefore, there appear to be different mechanisms regulating CC and CXC chemokine secretion by macrophages, depending on the stimulus and that TNFalpha and LPS can use different signaling mechanisms in macrophages to regulate chemokine synthesis.

Cells, Cultured↗
PubMed1990

Impairment of macrophage colony-stimulating factor production and lack of resident bone marrow macrophages in the osteopetrotic op/op mouse.

Mouse calvaria-derived osteoblastlike cells have been shown to produce macrophage colony-stimulating factor (M-CSF). This factor may be involved in osteoclastogenesis and thus in bone resorption. In the present study we investigated whether the production of M-CSF was altered in the osteopetrotic mouse mutant strain op/op, characterized by a decrease in osteoclast number and an impairment of bone resorption. Whole calvariae and cells, as well as skin and lung fibroblasts, of the op/op mouse were found to produce no measurable M-CSF, in contrast to tissue and cells derived from normal littermates. M-CSF was identified by colony assay in semisolid media and by inhibition of the biologic activity with antiserum against M-CSF. Furthermore, the number of resident macrophages, identified by F4/80 antigen (F4/80 Ag) immunohistochemistry, was drastically decreased in bone and bone marrow of the op/op mouse, but in skin these cells were normal in number and morphology. These findings suggest that both M-CSF and resident macrophages play a role in the mechanism of bone resorption. The op/op mouse appears to be a valuable model to further investigate such a hypothesis.

Animals↗
PubMed1990

Effects of interleukin 3 and of granulocyte-macrophage and macrophage colony stimulating factors on osteoclast differentiation from mouse hemopoietic tissue.

The effects of granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF), and interleukin 3 (IL3) on osteoclast formation were tested by incubation of murine hemopoietic cells on plastic coverslips and bone slices with GM-CSF, M-CSF, or IL3, with or without 1,25(OH)2 vitamin D3 (1,25(OH)2D3). Osteoclastic differentiation was detected after incubation by scanning electron microscopical examination of bone slices for evidence of osteoclastic excavations, and by autoradiographic assessment of cells for 1,25(OH)2D3-calcitonin (CT) binding. The differentiation of CT-receptor-positive cells preceded bone resorption, but the number that developed correlated with the extent of bone resorption (r = 0.88). M-CSF and GM-CSF substantially reduced bone resorption and CT-receptor-positive cell formation. The degree of inhibition of bone resorption could not be attributed to effects on the function of mature cells, since M-CSF inhibits resorption by such cells only by 50%, and GM-CSF has no effect. GM-CSF inhibited the development of mature function (bone resorption) to a greater extent than it inhibited CT-receptor-positive cell formation. Since CT-receptor expression antedated resorptive function, this suggests that GM-CSF resulted in the formation of reduced numbers of relatively immature osteoclasts. This suggests that it may exert a restraining effect on the maturation of cells undergoing osteoclastic differentiation in response to 1,25(OH)2D3. Conversely, IL3, which also has no effect on mature osteoclasts, by itself induced CT-receptor expression but not bone resorption; in combination with 1,25(OH)2D3 it induced a threefold increase in bone resorption and CT-receptor-positive cells compared with cultures incubated with 1,25(OH)2D3 alone. IL3 did not induce CT-receptors in peritoneal macrophages, blood monocytes, or J 774 cells. The results suggest that IL3 induces only partial maturation of osteoclasts, which is augmented or completed by additional factors such as 1,25(OH)2D3.

Animals↗