Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients.
OBJECTIVE
Rheumatoid arthritis (RA) is a chronic inflammatory disorder of unknown origin. Histone deacetylase (HDA) activity is considered to play a major role in the transcriptional regulation of proinflammatory genes. We undertook this study to investigate the balance of histone acetylase and HDA activity in synovial tissue from RA patients compared with that from patients with osteoarthritis (OA) and normal controls.


METHODS
Activity of histone acetylases and HDAs was measured in nuclear extracts of total synovial tissue samples, which were obtained from RA and OA patients undergoing surgical joint replacement, and compared with the activity in synovial tissues from patients without arthritis. Tissue expression of HDAs 1 and 2 was quantified by Western blotting. In addition, immunohistochemistry was performed for HDA-2.


RESULTS
Mean+/-SEM HDA activity in synovial tissue samples derived from patients with RA was measured as 1.5+/-0.3 micromoles/microg, whereas the activity levels in OA (3.2+/-0.7 micromoles/microg) and normal (7.1+/-4.2 micromoles/microg) synovial tissue samples were significantly higher. Histone acetylase activity reached similar levels in RA and OA tissues and in normal tissues. The ratio of HDA activity to histone acetylase activity in RA synovial tissue was significantly reduced (12+/-2%) compared with that in OA synovial tissue (26+/-3%). The activity ratio in normal control samples was arbitrarily set at 100+/-40%. In addition, the tissue expression of HDA-1 and HDA-2 proteins was clearly lower in RA samples than in OA samples.


CONCLUSIONS
The balance of histone acetylase/HDA activities is strongly shifted toward histone hyperacetylation in patients with RA. These results offer novel molecular insights into the pathogenesis of the disease that might be relevant to the development of future therapeutic approaches.
Huber
Lars C
LC
Center of Experimental Rheumatology, University Hospital Zurich, and Zurich Center of Integrative Human Physiology, Zurich, Switzerland. Lars.Huber@usz.ch
Brock
Matthias
M
Hemmatazad
Hossein
H
Giger
Olivier T
OT
Moritz
Falk
F
Trenkmann
Michelle
M
Distler
Jörg H W
JH
Gay
Renate E
RE
Kolling
Christoph
C
Moch
Holger
H
Michel
Beat A
BA
Gay
Steffen
S
Distler
Oliver
O
Jüngel
Astrid
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000201:enzymology*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000201:enzymology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D051548:Histone Acetyltransferases / Q000378:metabolism*; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000201:enzymology*; D012097:Repressor Proteins / Q000378:metabolism*; D013583:Synovial Membrane / Q000201:enzymology*
D012097:Repressor Proteins; D051548:Histone Acetyltransferases; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases