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.


CONCLUSIONS
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.
Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea.
Hwa-Suk
HS
Lee
Seong Ji
SJ
Woo
Hyoung-Won
HW
Koh
Sun-O
SO
Ka
Lu
L
Zhou
Kyu Yun
KY
Jang
Hye Song
HS
Lim
Hyun-Ok
HO
Kim
Sang-Il
SI
Lee
Byung-Hyun
BH
Park
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D018972:Insulin-Like Growth Factor Binding Protein 3; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D020782:Matrix Metalloproteinases