Disease relevance of Csf1

• Increased Myeloid Cell Responses to M-CSF and RANKL Cause Bone Loss and Inflammation in SH3BP2 "Cherubism" Mice [1].
• M-CSF mediates TNF-induced inflammatory osteolysis [2].
• Although bone resorption and osteoclast numbers are reduced in osteopetrotic (op/op) mice, osteoclasts are nevertheless present and functional, despite the absence of macrophage colony-stimulating factor (M-CSF) [3].
• Like M-CSF-deficient mice, they have osteopetrosis and are toothless because of failure of incisor eruption [4].
• Continuous or pulse exposure of murine bone marrow cells to pertussis toxin inhibited CSF-1 or IL 3-induced colony formation by approximately 50% [5].

Psychiatry related information on Csf1

• Interestingly, however, in the nerve treated with tumor necrosis factor-alpha (but not in the nerve treated with colony stimulating factor-1) this increase was accompanied by an increased permissiveness of the nerve to neuronal adhesion, which we examined in vitro using longitudinal sections of the nerve on which PC12 cells were seeded [6].
• In a series of 145 cases with neurological diseases, macrophage-colony stimulating factor (M-CSF) was detected in cerebrospinal fluid of patients with brain tumors, bacterial meningitis, and less frequently, AIDS-dementia complex [7].
• Macrophage colony stimulating factor (M-CSF) and its receptor are upregulated in the brain in Alzheimer's disease [8].
• In this study, to detect the critical period, we administered an antagonistic antibody directed against c-Fms, a receptor for M-CSF, to inbred C57BL/6 mice for various periods [9].

High impact information on Csf1

• Both CSF-1 and GM-CSF are responsible for transition of cells of the M phi lineage from bone marrow to blood, and from blood to tissues, and have a critical extramedullary role [10].
• A hypothetical major role of CSF-1-independent M phi is to collaborate with lymphocytes in mounting an immune response [10].
• M-CSF and RANKL stimulation of myeloid cells that overexpress wild-type SH3BP2 results in similar large osteoclasts [1].
• This indicates that the mutant phenotype reflects gain of SH3BP2 function and suggests that SH3BP2 is a critical regulator of myeloid cell responses to M-CSF and RANKL stimulation [1].
• Enforced expression of Bcl-2 in monocytes rescues macrophages and partially reverses osteopetrosis in op/op mice [11].

Chemical compound and disease context of Csf1

• Proteinuria rose progressively in both groups but did not differ between them (urine protein/creatinine ratio at 3 days: 1.01 +/- 0.38 in op/op versus 1.45 +/- 0.43 in op/+; P, not significant) [12].
• The increased susceptibility of the op/op mice to E. coli fecal peritonitis was not due to their possible increased sensitivity to endotoxin, since the mutant mice tolerated lipopolysaccharide doses more than twice those tolerated by control littermates [13].
• Addition of PTH or 1,25-(OH)2D3 together with M-CSF induced both osteoclastogenesis and bone resorption [14].
• Our findings clearly illustrate the importance of both M-CSF and M-CSF-dependent monocytes/Mphis in maintaining cholesterol homeostasis and in atherogenesis [15].
• Ovariectomy failed to induce bone loss, stimulate bone resorption, or increase M-CSF- and RANKL-dependent osteoclastogenesis in T-cell deficient mice, establishing T cells as essential mediators of the bone-wasting effects of estrogen deficiency in vivo [16].

Biological context of Csf1

• TNF-alpha stimulated M-CSF gene expression, in vivo, only in the presence of TNF-responsive stromal cells [2].
• Comparative effects in vivo of recombinant murine interleukin 3, natural murine colony-stimulating factor-1, and recombinant murine granulocyte-macrophage colony-stimulating factor on myelopoiesis in mice [17].
• Nevertheless, all four of the mRNAs induced by CSF-1 in arrested cultures of 2F5 were strongly induced with the same kinetics in these cycling cells [18].
• Temporal expression and location of colony-stimulating factor 1 (CSF-1) and its receptor in the female reproductive tract are consistent with CSF-1-regulated placental development [19].
• The narrow bone marrow cavity in the op/opFlt1(TK)-/- mice was gradually replaced with fibrous tissue, resulting in severe marrow hypoplasia and extramedullary hematopoiesis [20].

Anatomical context of Csf1

• When mouse bone marrow cells were cultured with M-CSF, M-CSF-dependent bone marrow macrophages (M-BMM phi) appeared within 3 d [21].
• Severe deficiency of osteoclasts, monocytes, and peritoneal macrophages in osteopetrotic (op/op) mutant mice is caused by the absence of functional macrophage colony-stimulating factor (M-CSF) [22].
• These results indicate that both contact with stromal cells and M-CSF are requisite for osteoclast differentiation under physiological conditions [22].
• To clarify the role of M-CSF in the osteoclast differentiation, we established a clonal stromal cell line OP6L7 capable of supporting hemopoiesis from newborn op/op mouse calvaria [22].
• Early gene expression associated with the mitogenic response to colony stimulating factor-1 (CSF-1) has been examined in BAC1.2F5, a CSF-1-dependent murine macrophage cell line [18].

Associations of Csf1 with chemical compounds

• Tartrate-resistant acid phosphatase-positive osteoclasts were also formed when M-BMM phi were further cultured for 3 d with mouse tumor necrosis factor alpha (TNF-alpha) in the presence of M-CSF [21].
• IgG and NADPH increased the transcription rates for JE/MCP-1 and CSF-1, effects inhibited by TMTU [23].
• The receptor for the macrophage colony stimulating factor-1 (CSF-1R) is a transmembrane glycoprotein with intrinsic tyrosine kinase activity [24].
• However, CSF-1 failed to prime NOD M phi s to completely differentiate in response to gamma-interferon, as shown by their decreased lipopolysaccharide-stimulated interleukin 1 secretion [25].
• By contrast, the mature cell surface glycoprotein encoded by the v-fms oncogene was phosphorylated on tyrosine in the absence of CSF-1, suggesting that it functions as a ligand-independent kinase [26].

Physical interactions of Csf1

• Specific structural proteins associated with the separate CSF-1R multimeric complexes upon CSF-1 stimulation and the presence of the distinct pools of the CSF-1R were dependent on the integrity of the microtubular network [27].
• To test this hypothesis, murine bone marrow macrophages were cultured under conditions that down-regulate M-CSFr and the effect of IL-4 on the reexpression of the receptor measured by binding of 125I-labeled M-CSF to the cells [28].
• Our novel results are consistent with the notion that specific receptors for epo exist on the cell surface of PEM and that binding of epo sets in motion a series of cellular events resulting in the internalization of CSF-1 receptors [29].
• CSF-1 induced binding of Elk-1 to the fos gene serum response element appears to be part of the molecular mechanism by which this occurs [30].
• They also show a complete disappearance of the colony-stimulating factor 1 (CSF-1) receptor that occurs shortly after the binding of TNF-alpha by the trophectoderm [31].

Enzymatic interactions of Csf1

• P130 and SHPTP1 are further tyrosyl phosphorylated upon CSF-1 stimulation [32].
• Association between phosphatidylinositol-3 kinase, Cbl and other tyrosine phosphorylated proteins in colony-stimulating factor-1-stimulated macrophages [33].
• Their c-fms proteins were normally phosphorylated on serine and became phosphorylated on tyrosine residues contained in five tryptic peptides when the cells were exposed to M-CSF [34].
• 1,25-Dihydroxyvitamin D3 and macrophage colony-stimulating factor-1 synergistically phosphorylate talin [35].
• In peritoneal macrophages, ERK kinase activity was stimulated and cPLA2 was phosphorylated and activated in response to CSF-1 [36].

Regulatory relationships of Csf1

• Transduction of c-fms into PU.1 -/- myeloid progenitors bypasses the block to M-CSF-dependent proliferation but does not induce detectable macrophage differentiation [37].
• Cachectin/tumor necrosis factor transiently induced the expression of CSF-1 and inhibited the differentiation of H-1/A cells into adipocytes [38].
• Phosphatidylcholine hydrolysis and c-myc expression are in collaborating mitogenic pathways activated by colony-stimulating factor 1 [39].
• Using primary bone marrow-derived macrophages from me/me mice and normal littermates, we examined the role of SHPTP1 in regulating signaling by the major macrophage mitogen colony-stimulating factor 1 (CSF-1) (also known as macrophage colony-stimulating factor) [32].
• The soluble form of ODF (sODF) induces the differentiation of osteoclast precursors into osteoclasts in the presence of M-CSF [40].

Other interactions of Csf1

• However, at 21 degrees C or 37 degrees C, Multi-CSF inhibits binding of the other three CSFs and GM-CSF inhibits binding of G-CSF and M-CSF [41].
• Stimulation of arrested cells by CSF-1 resulted in acute, transient elevation in c-fos and subsequently in c-myc mRNA levels [18].
• Activation of Src family kinases by colony stimulating factor-1, and their association with its receptor [24].
• The failure of PU.1 -/- progenitors to respond to M-CSF is due to lack of c-fms gene transcription [37].
• CSF-1 stimulation of NOD marrow induced Møs to differentiate to the point that they secreted levels of tumor necrosis factor alpha equivalent to that of controls [25].

Analytical, diagnostic and therapeutic context of Csf1

• The dissection of the system has been greatly facilitated by discovery of the osteopetrotic op/op mouse, which has a spontaneous knockout of the gene for CSF-1 and possesses generalized but differential deficiency of various local subpopulations of M phi [10].
• CSF-1 mRNA, predominantly the 2.3-kilobase (kb) form, was first detected by in situ hybridization in uterine epithelium prior to implantation on day 3 and subsequently increased, reaching a peak at days 14-15 [19].
• X-irradiation to doses that decreased CSF-1 to 40% of control levels (greater than 5,000 rad) resulted in a 30-fold increase in growth of FDCP-1 or bg/bg cl 1 cells in liquid co-culture or agar culture overlay with no detectable growth of 32D cl 3 [42].
• Southern blot analysis of tumor DNA from six of six of these tumors failed to reveal any rearrangements in the genes for CSF-1 or the CSF-1R [43].
• Colony-stimulating factor-1 antisense treatment suppresses growth of human tumor xenografts in mice [44].

References