title: Inhibition of each module of connective tissue growth factor as a potential therapeutic target for rheumatoid arthritis.
abstract: We previously reported the importance of connective tissue growth factor (CTGF) in rheumatoid arthritis (RA). CTGF contains four distinct modules connected in tandem, namely insulin-like growth factor-binding protein (IGFBP)-like, von Willebrand factor (vWF) type C repeat, thrombospondin type 1 (TSP-1) repeat, and carboxyl-terminal (CT) modules. The relationships between each of these modules of CTGF and RA remain unknown. Here, we analyzed how inhibition of each CTGF module affects the pathophysiology of RA. We conducted stimulation and suppression experiments on synovial cells (MH7A) obtained from patients with RA. Moreover, we examined angiogenesis by means of a tube-formation assay performed using human umbilical vein endothelial cells (HUVECs), and we used tartrate-resistant acid phosphatase (TRAP) staining to analyze osteoclastogenesis. Our results showed that M-CSF/RANKL-mediated osteoclastogenesis was enhanced when CTGF was added, but the effect of CTGF was neutralized by mAbs against CTGF modules 1-4. Furthermore, CTGF treatment of HUVECs induced formation of tubular networks, which resulted in acceleration of the angiogenesis of RA synoviocytes, and quantification showed that this tubular-network formation was also disrupted by anti-CTGF module 1-4 mAbs. Lastly, TNF-α enhanced the expression of CTGF and matrix metalloproteinase-3 (MMP3) in MH7A cells, and this enhancement was potently neutralized by mAbs against CTGF modules 1, 3 and 4. Thus, our results indicate that not only a mAb against CTGF but also mAbs against each specific module of CTGF might serve as potential therapeutic agents in the treatment of RA.
authors.affiliation: a Institute for Environment and Gender Specific Medicine, Juntendo University Graduate School of Medicine , Chiba , Japan .|b Department of Internal Medicine and Rheumatology , School of Medicine, Juntendo University , Tokyo , Japan .
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyashita
authors.affiliation: a Institute for Environment and Gender Specific Medicine, Juntendo University Graduate School of Medicine , Chiba , Japan .|c Department of Internal Medicine and Rheumatology , Juntendo University Urayasu Hospital , Chiba , Japan .
authors.forename: Shinji
authors.initials: S
authors.lastname: Morimoto
authors.affiliation: a Institute for Environment and Gender Specific Medicine, Juntendo University Graduate School of Medicine , Chiba , Japan .
authors.forename: Maki
authors.initials: M
authors.lastname: Fujishiro
authors.affiliation: a Institute for Environment and Gender Specific Medicine, Juntendo University Graduate School of Medicine , Chiba , Japan .
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hayakawa
authors.affiliation: a Institute for Environment and Gender Specific Medicine, Juntendo University Graduate School of Medicine , Chiba , Japan .|b Department of Internal Medicine and Rheumatology , School of Medicine, Juntendo University , Tokyo , Japan .
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: a Institute for Environment and Gender Specific Medicine, Juntendo University Graduate School of Medicine , Chiba , Japan .|c Department of Internal Medicine and Rheumatology , Juntendo University Urayasu Hospital , Chiba , Japan .
authors.forename: Keigo
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: d Central Research Laboratories, Kissei Pharmaceutical Co Ltd , Nagano , Japan , and.
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyazawa
authors.affiliation: e Nosan Corporation , Kanagawa , Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Morioka
authors.affiliation: a Institute for Environment and Gender Specific Medicine, Juntendo University Graduate School of Medicine , Chiba , Japan .
authors.forename: Kenji
authors.initials: K
authors.lastname: Takamori
authors.affiliation: a Institute for Environment and Gender Specific Medicine, Juntendo University Graduate School of Medicine , Chiba , Japan .
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: a Institute for Environment and Gender Specific Medicine, Juntendo University Graduate School of Medicine , Chiba , Japan .|c Department of Internal Medicine and Rheumatology , Juntendo University Urayasu Hospital , Chiba , Japan .
authors.forename: Iwao
authors.initials: I
authors.lastname: Sekigawa
authors.affiliation: b Department of Internal Medicine and Rheumatology , School of Medicine, Juntendo University , Tokyo , Japan .
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Takasaki
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism*; D001862:Bone Resorption / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects*; D053245:RANK Ligand / Q000494:pharmacology; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D053245:RANK Ligand; D055513:Connective Tissue Growth Factor; D016173:Macrophage Colony-Stimulating Factor; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3
keywords: Angiogenesis; osteoclastogenesis; synoviocytes; therapy