Abstract
In rheumatoid arthritis (RA), hematopoietic progenitor cells (HPC) have age-inappropriate telomeric shortening suggesting premature senescence and possible restriction of proliferative capacity. In response to hematopoietic growth factors RA-derived CD34(+) HPC expanded significantly less than age-matched controls. Cell surface receptors for stem cell factor (SCF), Flt 3-Ligand, IL-3 and IL-6 were intact in RA HPC but the cells had lower transcript levels of cell cycle genes, compatible with insufficient signal strength in the ERK pathway. Cytokine-induced phosphorylation of ERK1/2 was diminished in RA HPC whereas phosphorylated STAT3 and STAT5 molecules accumulated to a similar extent as in controls. Confocal microscopy demonstrated that the membrane-proximal colocalization of K-Ras and B-Raf was less efficient in RA-derived CD34(+) cells. Thus, hyporesponsiveness of RA HPC to growth factors results from dampening of the ERK signaling pathways; with a defect localized in the very early steps of the ERK signaling cascade.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, CD34 / metabolism
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Arthritis, Rheumatoid / genetics
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Arthritis, Rheumatoid / metabolism
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Arthritis, Rheumatoid / physiopathology*
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Cell Proliferation*
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Cyclins / genetics
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Cytokines / pharmacology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Flow Cytometry
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Gene Expression Profiling
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Hematopoietic Cell Growth Factors / pharmacology
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism
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Hematopoietic Stem Cells / physiology*
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Humans
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Interleukin-3 Receptor alpha Subunit / metabolism
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Interleukin-6 Receptor alpha Subunit / metabolism
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MAP Kinase Signaling System / genetics
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MAP Kinase Signaling System / physiology*
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Male
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Microscopy, Confocal
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Middle Aged
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-kit / metabolism
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Proto-Oncogene Proteins c-myc / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor / metabolism
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STAT5 Transcription Factor / metabolism
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fms-Like Tyrosine Kinase 3 / metabolism
Substances
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Antigens, CD34
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Cyclins
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Cytokines
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Hematopoietic Cell Growth Factors
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Interleukin-3 Receptor alpha Subunit
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Interleukin-6 Receptor alpha Subunit
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Proto-Oncogene Proteins c-myc
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STAT3 Transcription Factor
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STAT5 Transcription Factor
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Proto-Oncogene Proteins c-kit
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fms-Like Tyrosine Kinase 3
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Extracellular Signal-Regulated MAP Kinases