Regulation of Apoptosis and Inflammatory Responses by Insulin‐like Growth Factor Binding Protein 3 in Fibroblast‐like Synoviocytes and Experimental Animal Models of Rheumatoid Arthritis

Objective Insulin‐like growth factor binding protein 3 (IGFBP‐3) is known to interfere with the NF‐κB signaling pathway, and it effectively promotes apoptosis in tumor cells by a variety of mechanisms. NF‐κB activation and apoptosis resistance of fibroblast‐like synoviocytes (FLS) play pivotal roles in rheumatoid arthritis (RA). This study was undertaken to evaluate whether IGFBP‐3 has antiarthritic effects. Methods To deliver IGFBP‐3, we used an adenovirus containing IGFBP‐3 complementary DNA (AdIGFBP‐3) or IGFBP‐3 mutant that is devoid of IGF binding affinity but retains IGFBP‐3 receptor binding ability (AdmtIGFBP‐3). The regulatory roles of IGFBP‐3 in inflammation and bone destruction were investigated in mice with collagen‐induced arthritis (CIA). Results IGFBP‐3 levels were significantly higher in patients with RA than in those with osteoarthritis (OA) and were notably higher in patients with active RA. AdIGFBP‐3 suppressed NF‐κB activation, chemokine production, and matrix metalloproteinase secretion induced by tumor necrosis factor α (TNFα) in RA FLS. AdIGFBP‐3 sensitized RA FLS to TNFα‐induced apoptosis in vitro and also significantly increased apoptosis in an in vivo model of Matrigel implants engrafted into immunodeficient mice. AdIGFBP‐3–injected mice with CIA had attenuated arthritis severity and reduced radiologic and pathologic abnormalities. Moreover, AdIGFBP‐3 down‐regulated local and systemic levels of NF‐κB–targeted proinflammatory cytokines. Of note, RA FLS and mice with CIA treated with AdmtIGFBP‐3 exhibited similar effects as those treated with AdIGFBP‐3. Conclusion Our results suggest that both the inflammatory response and bone destruction are reduced with blockage of NF‐κB activation and induction of apoptosis in RA FLS by IGFBP‐3. Therefore, IGFBP‐3 may have therapeutic potential in RA.