title: Dampened ERK signaling in hematopoietic progenitor cells in rheumatoid arthritis.
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.
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University, USA.
authors.forename: Inés
authors.initials: I
authors.lastname: Colmegna
authors.forename: Sergey
authors.initials: S
authors.lastname: Pryshchep
authors.forename: Hisashi
authors.initials: H
authors.lastname: Oishi
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D049109:Cell Proliferation; D016213:Cyclins / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D053650:Interleukin-3 Receptor alpha Subunit / Q000378:metabolism; D053698:Interleukin-6 Receptor alpha Subunit / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D016213:Cyclins; D016207:Cytokines; D016298:Hematopoietic Cell Growth Factors; D053650:Interleukin-3 Receptor alpha Subunit; D053698:Interleukin-6 Receptor alpha Subunit; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3; D048049:Extracellular Signal-Regulated MAP Kinases