THU0099 Adenovirus-Mediated IGFBP-3 Gene Transfer Induces Apoptosis and Suppresses Inflammation and Bone Destruction in Rheumatoid Arthritis

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.

References

Feldmann M, Brennan FM, Maini RN. Rheumatoid arthritis. Cell 1996;85(3):307-10. Muller-Ladner U, Pap T, Gay RE, Neidhart M, Gay S. Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis. Nat Clin Pract Rheumatol 2005;1(2):102-10. Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev2010;233(1):233-55. Noss EH, Brenner MB. The role and therapeutic implications of fibroblast-like synoviocytes in inflammation and cartilage erosion in rheumatoid arthritis. Immunol Rev2008;223:252-70. Baier A, Meineckel I, Gay S, Pap T. Apoptosis in rheumatoid arthritis. Curr Opin Rheumatol 2003;15(3):274-9. Hah YS, Lee YR, Jun JS, Lim HS, Kim HO, Jeong YG, et al. A20 suppresses inflammatory responses and bone destruction in human fibroblast-like synoviocytes and in mice with collagen-induced arthritis. Arthritis Rheum2010;62(8):2313-21.

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