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