Human macrophage colony‐stimulating factor heterogeneity results from alternative mRNA splicing, differential glycosylation, and proteolytic processing

Shadle, P. J.; Aldwin, Lois; Nitecki, Danute E.; Koths, Kirston

doi:10.1002/jcb.240400110

Cited by 18 publications

(11 citation statements)

References 49 publications

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“…Although CSF-1 is derived from a single-copy gene, there is considerable heterogeneity in protein size and structure due to a combination of alternative mRNA splicing, glycosylation, and proteolytic processing (37). The multiple CSF-1 mRNA species identified in human and murine tissues arise as a result of alternative splicing in exon 6 and the alternative use of exons 9 and 10 in the 3Ј-untranslated region of the gene.…”

Section: Discussionmentioning

confidence: 99%

The Cell-surface Form of Colony-stimulating Factor-1 Is Regulated by Osteotropic Agents and Supports Formation of Multinucleated Osteoclast-like Cells

Yao

Sun

Hammond

et al. 1998

Journal of Biological Chemistry

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Colony-stimulating factor-1 (CSF-1) is a hematopoietic growth factor that is released by osteoblasts and is recognized to play a critical role in bone remodeling in vivo and in vitro. CSF-1 is synthesized as a soluble or cellsurface protein. It is unclear, however, whether human osteoblasts express both molecular forms of CSF-1, and whether these isoforms can independently mediate osteoclastogenesis. In the present study, using a combination of quantitative reverse transcriptase polymerase chain reaction, flow cytometry, and Western immunoblot analysis, we have demonstrated that human osteoblast-like cells as well as primary human osteoblasts express the cell-surface form of CSF-1 both constitutively and in response to parathyroid hormone and tumor necrosis factor. Furthermore, using an in vitro coculture system, we have shown that cell-surface CSF-1 alone is sufficient to support osteoclast formation. These findings may be especially significant in view of evidence that direct cell-to-cell contact is critical for osteoclast formation, and suggest that differential regulation of expression of the CSF-1 isoforms may influence osteoclast function modulated by osteotropic hormones.The precise mechanism whereby osteoblasts mediate osteoclastic bone resorption is unclear. One widely held hypothesis is that activated osteoblasts secrete cytokines that directly or indirectly influence osteoclast formation or function (1). Although the exact nature of all of these cytokines is unknown, compelling in vivo and in vitro data have emerged to support a role for colony-stimulating factor-1 (CSF-1) 1 as an osteoblastderived factor involved in osteoclast formation. Thus, in vivo, deficiency of CSF-1 in the op/op osteopetrotic mouse causes a failure of osteoclast formation and bone resorption (2-4), while in vitro studies have demonstrated that CSF-1 is critical for the proliferation and differentiation of osteoclast progenitors (5, 6), that CSF-1 stimulates bone resorption in the fetal mouse metacarpal assay (7), and that CSF-1 receptors are present on osteoclasts (8, 9). Additionally, we have reported that CSF-1 is the principal colony-stimulating activity released from osteoblasts constitutively and in response to PTH and parathyroid hormone-related protein (8). In support of a role for CSF-1 in bone remodeling in humans, Sarma et al. (10) have recently reported that, consistent with studies in mice, recombinant human CSF-1 induces osteoclastogenesis and bone resorption in human marrow cultures.Multiple human CSF-1 mRNA species (4.0, 3.0, 2.3, 1.9, and 1.6 kb) are expressed by the CSF-1 gene (11-15), and molecular cloning of cDNAs derived from these transcripts has demonstrated that the size differences are due to alternative splicing in exon 6 and the alternative use of the 3Ј-end exons 9 or 10 (11-13). A combination of nucleotide sequence analysis and transfection studies indicates that two distinct CSF-1 protein products are encoded by these transcripts. Both primary translation products are membrane-bound glycoproteins t...

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Section: Discussionmentioning

confidence: 99%

The Cell-surface Form of Colony-stimulating Factor-1 Is Regulated by Osteotropic Agents and Supports Formation of Multinucleated Osteoclast-like Cells

Yao

Sun

Hammond

et al. 1998

Journal of Biological Chemistry

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“…78 Alternate mRNA splicing and differential proteolytic processing gives rise to three biologicallyactive isoforms of CSF-1: a secreted glycoprotein; a secreted proteoglycan; and a membrane spanning cell-surface glycoprotein. 82 The two major cell populations regulated by CSF-1 via expression of the CSF-1R are cells of the trophoblast lineage and hemopoietic cells of the mononuclear phagocyte system, 83 with distinct promoters specific to each lineage in humans. 84 Expression beyond these lineages is also reported in settings including Paneth cells of the small intestine, 85,86 neural stem cells 87 and kidney tubular epithelium in a setting of acute injury.…”

Section: Csf-1 As a Developmental Mediatormentioning

confidence: 99%

Macrophages and CSF-1

Jones¹,

Ricardo

2013

Organogenesis

123

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“…Goldfish CSF-1 has 199 amino acids and was significantly smaller than the mammalian CSF-1 isoforms (secreted glycoprotein or the secreted/matrix bound proteoglycan form of mammalian CSF-1) and similar to the membrane-bound glycosylated form (20). Interestingly, all of these mammalian forms were shown to be functional where the first 150 amino acids were required for proper folding and function (21).…”

Section: Discussionmentioning

confidence: 99%

Growth Factors of Lower Vertebrates

Hanington¹,

Wang

Secombes

et al. 2007

Journal of Biological Chemistry

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Colony-stimulating factor-1 (CSF-1) regulates mononuclear cell proliferation, differentiation, and survival. The functions of CSF-1 are well documented in mammals; however, little is known about CSF-1 biology in lower vertebrates. This is the first report on the identification and functional characterization of a fish CSF-1 molecule expressed highly in the spleen and in phorbol 12-myristate 13-acetate-stimulated monocytes. Goldfish CSF-1 is a 199-amino acid protein that possesses the required cysteine residues to form important intra-chain and inter-chain disulfide bonds that allow CSF-1 to form a functional homodimer and to interact with its high affinity receptor, CSF-1R. Recombinant goldfish CSF-1 formed a homodimer and bound to the soluble goldfish CSF-1R. The addition of the recombinant CSF-1 to sorted goldfish progenitor cells, monocytes, and macrophages induced the differentiation of monocytes into macrophages and the proliferation of monocyte-like cells. The proliferation of these cells was abrogated by addition of an anti-CSF-1R antibody as well as the soluble CSF-1R. The ability of the soluble CSF-1R to inhibit CSF-1-induced proliferation represents a novel mechanism for the regulation of CSF-1 function.Colony-stimulating factor-1 (CSF-1) 2 is the primary growth factor involved in the regulation of survival, proliferation, and differentiation of mononuclear phagocytes and their precursors (1). CSF-1 has also been demonstrated to play important roles in bone metabolism, atherogenesis, inflammation, pregnancy, and in pre-implantation development of the female reproductive tract (2-4). All forms of CSF-1 initiate their effects by a high affinity interaction between the CSF-1 molecule, which is commonly active as a homodimer, and the CSF-1 receptor (CSF-1R) which is a member of the class III receptor tyrosine kinase family (5-8).From an evolutionary standpoint, macrophages and their functions are quite conserved; macrophage-like cells can be found in almost all multicellular organisms. Macrophage development is relatively unknown in almost all of these organisms with the exception of mammals. Until recently, mammals were the only group of organisms in which CSF-1 had been identified, and the suggestion that the CSF-1 pathway of macrophage development existed in organisms other than mammals was the identification of CSF-1 transcripts in the chicken (9, 10) and fish (11-13) as well as the identification of a CSF-1R in the goldfish (14), pufferfish (15), rainbow trout (16), zebrafish (17), and the gilthead sea bream (18).Here we describe the identification and biological characterization of the first CSF-1 from a nonmammalian organism, the goldfish. Goldfish CSF-1 was encoded for by a 600-bp open reading frame that translates into a predicted peptide of 199 amino acids. Although it had only a 27% amino acid identity with human CSF-1, important cysteine residues required for formation of the CSF-1 homodimer were conserved. Goldfish CSF-1 was highly expressed in the spleen, and its expression was up-regulated i...

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Human macrophage colony‐stimulating factor heterogeneity results from alternative mRNA splicing, differential glycosylation, and proteolytic processing

Cited by 18 publications

References 49 publications

The Cell-surface Form of Colony-stimulating Factor-1 Is Regulated by Osteotropic Agents and Supports Formation of Multinucleated Osteoclast-like Cells

The Cell-surface Form of Colony-stimulating Factor-1 Is Regulated by Osteotropic Agents and Supports Formation of Multinucleated Osteoclast-like Cells

Macrophages and CSF-1

Growth Factors of Lower Vertebrates

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