MDM4 overexpression contributes to synoviocyte proliferation in patients with rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic autoimmune disease with features of inflammatory cell infiltration, synovial cell invasive proliferation, and ultimately, irreversible joint destruction. It has been reported that the p53 pathway is involved in RA pathogenesis. MDM4/MDMX is a major negative regulator of p53. To determine whether MDM4 contributes to RA pathogenesis, MDM4 mRNA and protein expression were assessed in fibroblast-like synoviocytes (FLS) by real-time PCR, western blotting, and in synovial tissues by immunohistochemistry. Furthermore, MDM4 was knocked down and overexpressed by lentivirus-mediated expression, and the proliferative capacity of FLS was determined by MTS assay. We found that cultured FLS from RA and osteoarthritis (OA) patients exhibited higher levels of MDM4 mRNA and protein expression than those from trauma controls. MDM4 protein was highly expressed in the synovial lining and sublining cells from both types of arthritis. Finally, MDM4 knockdown inhibited the proliferation of RA FLS by enhancing functional p53 levels while MDM4 overexpression promoted the growth of RA FLS by inhibiting p53 effects. Taken together, our results suggest that the abundant expression of MDM4 in FLS may contribute to the hyperplasia phenotype of RA synovial tissues.
Xu
Nanwei
N
Department of Orthopaedics, The Affiliated Hospital of Nanjing Medical University, Changzhou Second People's Hospital, Changzhou 213003, PR China.
Wang
Yuji
Y
Li
Dawei
D
Chen
Guoqiang
G
Sun
Rongbin
R
Zhu
Ruixia
R
Sun
Sai
S
Liu
Hongwei
H
Yang
Guang
G
Dong
Tianhua
T
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53