Gadd45beta deficiency in rheumatoid arthritis: enhanced synovitis through JNK signaling.
OBJECTIVE
JNK-mediated cell signaling plays a critical role in matrix metalloproteinase (MMP) expression and joint destruction in rheumatoid arthritis (RA). Gadd45beta, which is an NF-kappaB-regulated gene, was recently identified as an endogenous negative regulator of the JNK pathway, since it could block the upstream kinase MKK-7. This study was carried out to evaluate whether low Gadd45beta expression in RA enhances JNK activation and overproduction of MMPs in RA, and whether Gadd45beta deficiency increases arthritis severity in passive K/BxN murine arthritis.


METHODS
Activation of the NF-kappaB and JNK pathways and Gadd45beta expression were analyzed in human synovium and fibroblast-like synoviocytes (FLS) using quantitative polymerase chain reaction, immunoblotting, immunohistochemistry, electrophoretic mobility shift assay, and luciferase reporter constructs. Gadd45beta(-/-) and wild-type mice were evaluated in the K/BxN serum transfer model of inflammatory arthritis, and clinical signs of arthritis, osteoclast formation, and bone erosion were assessed.


RESULTS
Expression levels of the Gadd45beta gene and protein were unexpectedly low in human RA synovium despite abundant NF-kappaB activity. Forced Gadd45beta expression in human FLS attenuated tumor necrosis factor-induced signaling through the JNK pathway, reduced the activation of activator protein 1, and decreased the expression of MMP genes. Furthermore, Gadd45beta deficiency exacerbated K/BxN serum-induced arthritis in mice, dramatically increased signaling through the JNK pathway, elevated MMP3 and MMP13 gene expression in the mouse joints, and increased the synovial inflammation and number of osteoclasts.


CONCLUSIONS
Deficient Gadd45beta expression in RA can contribute to activation of JNK, exacerbate clinical arthritis, and augment joint destruction. This process can be mitigated by enhancing Gadd45beta expression or by inhibiting the activity of JNK or its upstream regulator, MKK-7.
Svensson
Camilla I
CI
University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
Inoue
Tomoyuki
T
Hammaker
Deepa
D
Fukushima
Akihisa
A
Papa
Salvatore
S
Franzoso
Guido
G
Schett
Georg
G
Corr
Maripat
M
Boyle
David L
DL
Firestein
Gary S
GS
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D001168:Arthritis / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D048688:MAP Kinase Kinase 7 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology*; D013585:Synovitis / Q000378:metabolism* / Q000473:pathology; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3; D016328:NF-kappa B; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C482569:MAP2K7 protein, human