Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis.
OBJECTIVE
In rheumatoid arthritis (RA), telomeres of lymphoid and myeloid cells are age-inappropriately shortened, suggesting excessive turnover of hematopoietic precursor cells (HPCs). The purpose of this study was to examine the functional competence (proliferative capacity, maintenance of telomeric reserve) of CD34+ HPCs in RA.


METHODS
Frequencies of peripheral blood CD34+,CD45+ HPCs from 63 rheumatoid factor-positive RA patients and 48 controls matched for age, sex, and ethnicity were measured by flow cytometry. Proliferative burst, cell cycle dynamics, and induction of lineage-restricted receptors were tested in purified CD34+ HPCs after stimulation with early hematopoietins. Telomere sequences were quantified by real-time polymerase chain reaction. HPC functions were correlated with the duration, activity, and severity of RA as well as its treatment.


RESULTS
In healthy donors, CD34+ HPCs accounted for 0.05% of nucleated cells; their numbers were strictly age dependent and declined at a rate of 1.3% per year. In RA patients, CD34+ HPC frequencies were age-independently reduced to 0.03%. Upon growth factor stimulation, control HPCs passed through 5 replication cycles over 4 days. In contrast, RA-derived HPCs completed only 3 generations. Telomeres of RA CD34+ HPCs were age-inappropriately shortened by 1,600 bp. All HPC defects were independent of disease duration, disease activity, and smoking status, and were present to the same degree in untreated patients.


CONCLUSIONS
In RA, circulating bone marrow-derived progenitor cells were diminished, and concentrations stagnated at levels typical of those in old control subjects. HPCs from RA patients displayed growth factor nonresponsiveness and sluggish cell cycle progression; marked telomere shortening indicated proliferative stress-induced senescence. Defective HPC function independent of disease activity markers suggests bone marrow failure as a potential pathogenic factor in RA.
Colmegna
Inés
I
Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Diaz-Borjon
Alejandro
A
Fujii
Hiroshi
H
Schaefer
Linda
L
Goronzy
Jörg J
JJ
Weyand
Cornelia M
CM
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000235:genetics; D016022:Case-Control Studies; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016615:Telomere / Q000235:genetics*