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

Abstract

Objective. Insulin-like growth factor binding protein 3 (IGFBP-3) is known to interfere with the NF-kappa B signaling pathway, and it effectively promotes apoptosis in tumor cells by a variety of mechanisms. NF-kappa B 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-kappa B activation, chemokine production, and matrix metalloproteinase secretion induced by tumor necrosis factor alpha (TNF alpha) in RA FLS. AdIGFBP-3 sensitized RA FLS to TNF alpha-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-kappa B-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-kappa B activation and induction of apoptosis in RA FLS by IGFBP-3. Therefore, IGFBP-3 may have therapeutic potential in RA.