Enhanced generation of endothelial cells from CD34+ cells of the bone marrow in rheumatoid arthritis: possible role in synovial neovascularization.
OBJECTIVE
To examine the capacity of bone marrow CD34+ cells to generate endothelial cells, in order to assess the role of bone marrow in neovascularization in the synovium of rheumatoid arthritis (RA).


METHODS
CD34+ cells purified from the bone marrow of 13 patients with active RA and 9 control subjects (7 osteoarthritis [OA] patients and 2 healthy individuals) were cultured in the presence of stem cell factor (10 ng/ml) and granulocyte-macrophage colony-stimulating factor (1 ng/ml). After 18 days of incubation, the generation of endothelial cells was assessed by flow cytometry. The generation of endothelial cells was compared with the degree of vascularization in the synovial tissues and with the microvessel densities in the synovium, as determined by microscopy. The expression of vascular endothelial growth factor receptor 2/kinase insert domain receptor (KDR) messenger RNA (mRNA) in CD34+ cells was examined by quantitative reverse transcription-polymerase chain reaction.


RESULTS
The generation of CD14+ cells from bone marrow-derived CD34+ cells from RA patients was comparable to that from control subjects. However, the generation of von Willebrand factor (vWF)-positive cells and CD31+/vWF+ cells from RA bone marrow-derived CD34+ cells was significantly higher than that from control subjects (P = 0.004 and P = 0.030, respectively). The generation of vWF+ cells from bone marrow CD34+ cells correlated significantly with the microvessel densities in the synovial tissues (r = 0.569, P = 0.021). Finally, RA bone marrow CD34+ cells expressed KDR mRNA at higher levels than OA bone marrow CD34+ cells.


CONCLUSIONS
These results indicate that RA bone marrow CD34+ cells have enhanced capacities to differentiate into endothelial cells in relation to synovial vascularization. The data therefore suggest that bone marrow CD34+ cells might contribute to synovial neovascularization by supplying endothelial precursor cells and, thus, play an important role in the pathogenesis of RA.
Hirohata
Shunsei
S
Teikyo University School of Medicine, Tokyo, Japan. shunsei@med.teikyo-u.ac.jp
Yanagida
Tamiko
T
Nampei
Akihide
A
Kunugiza
Yasuo
Y
Hashimoto
Hideo
H
Tomita
Tetsuya
T
Yoshikawa
Hideki
H
Ochi
Takahiro
T
D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation; D002469:Cell Separation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D019089:Stem Cell Factor / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology; D013583:Synovial Membrane / Q000098:blood supply* / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
D018952:Antigens, CD34; D012333:RNA, Messenger; D019089:Stem Cell Factor; D014841:von Willebrand Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D040301:Vascular Endothelial Growth Factor Receptor-2