Expression and function of histone deacetylases in rheumatoid arthritis synovial fibroblasts.
OBJECTIVE
To explore the effects of histone deacetylases (HDAC) on rheumatoid arthritis synovial fibroblasts (RA-SF).


METHODS
The expression of mRNA encoding HDAC1 through HDAC11 in RA-SF and osteoarthritis-SF (OA-SF) was determined using real-time polymerase chain reactions. The functions of HDAC1 and HDAC2 in RA-SF were assessed using small interfering RNA (siRNA) technology. Cell counts and proliferation were examined by MTT assays and BrDU ELISA, respectively, and apoptosis was determined using the TUNEL assay and annexin V staining. Levels of cell cycle-related molecules and matrix metalloproteinases (MMP) were tested by Western blotting and ELISA, respectively.


RESULTS
Messenger RNA expression of HDAC1 was significantly higher in RA-SF than in OA-SF. Knockdown of HDAC1 and HDAC2 by siRNA resulted in decreased cell counts and cell proliferation, and increased apoptosis in RA-SF. Expression of p16, p21, and p53 was increased by knockdown of both HDAC1 and HDAC2. On the other hand, knockdown of HDAC1, but not of HDAC2, upregulated tumor necrosis factor-alpha-induced MMP-1 production by RA-SF.


CONCLUSIONS
HDAC1 is overexpressed in RA-SF compared to OA-SF. HDAC1 supports cell proliferation and survival of RA-SF, but suppresses MMP-1 production. HDAC2 also plays an important role in cell proliferation and apoptosis of RA-SF. Our study provides useful information to develop new HDAC inhibitors for the treatment of RA.
Horiuchi
Marika
M
Department of Clinical Pathology and Immunology, Kobe University School of Medicine, Kobe, Japan.
Morinobu
Akio
A
Chin
Takaaki
T
Sakai
Yoshitada
Y
Kurosaka
Masahiro
M
Kumagai
Shunichi
S
D017209:Apoptosis / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002452:Cell Count; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000235:genetics*; D013583:Synovial Membrane / Q000378:metabolism / Q000503:physiopathology
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D020781:Matrix Metalloproteinase 1; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases