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THU0099 Adenovirus-Mediated IGFBP-3 Gene Transfer Induces Apoptosis and Suppresses Inflammation and Bone Destruction in Rheumatoid Arthritis
  1. S.-I. Lee1,
  2. Y.-H. Cheon1,
  3. H.-S. Lee2,
  4. B.-H. Park2,
  5. C.-H. Lee3,
  6. M. S. Lee3,
  7. W.-H. Yoo4
  1. 1Internal Medicine, Gyeongsang national university school of medicine, Jinju
  2. 2Biochemistry, Chonbuk National University Medical School, Jeonju
  3. 3Internal Medicine, School of medicine Wonkwang university, Iksan
  4. 4Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea, Republic of


Background Insulin-like growth factor binding protein-3 (IGFBP-3) is known to interfere NF-κB signaling pathway and effectively promotes apoptosis in tumor cells by a variety of mechanisms.

Objectives Due to the pivotal roles of NF-κB activation and apoptosis resistance of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA), we postulated that IGFBP-3 could have anti-arthritic effects.

Methods RA and osteoarthritis (OA) patients were recruited and IGFBP-3 levels were compared in the serum and synovial fluid. An adenovirus containing IGFBP-3 cDNA (Ad-IGFBP-3) or IGFBP-3 mutant devoid of IGF binding affinity but retains IGFBP-3 receptor binding ability (Ad-mtIGFBP-3) was used to deliver IGFBP-3. The regulatory roles of IGFBP-3 against inflammation and bone destruction were defined in mice with collagen-induced arthritis (CIA).

Results IGFBP-3 levels were higher in RA patients than OA, and much higher in active RA patients. Ad-IGFBP-3 suppressed NF-κB activation, chemokine production, and matrix metalloproteinase secretion induced by tumor necrosis factor-α (TNF-α) in RA-FLS. Ad-IGFBP-3 sensitized TNF-α-induced apoptosis of RA-FLS in vitro and also significantly increased apoptosis in vivo model of Matrigel implants engrafted into immunodeficient mice. Ad-IGFBP-3-injected CIA mice had an attenuated arthritis severity and reduced radiological and pathological abnormalities. Moreover, Ad-IGFBP-3 down-regulated local and systemic levels of NF-κB-targeted proinflammatory cytokines. Importantly, RA-FLS and CIA mice treated with Ad-mtIGFBP-3 exhibited similar effects as Ad-IGFBP3 did.

Conclusions These results suggest that blocking of NF-κB activation and induction of apoptosis in RA-FLS by IGFBP-3 reduce both inflammatory response and bone destruction. Therefore, IGFBP-3 may have a new therapeutic potential for the treatment of RA.


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Acknowledgements This work was supported by a grant from the National Research Foundation of Korea funded by the Korean government (No. 2012-0009319).

Disclosure of Interest None Declared

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