Catabolic effects of FGF-1 on chondrocytes and its possible role in osteoarthritis.
Fibroblast growth factor 1 (FGF-1) is a classical member of the FGF family and is produced by chondrocytes cultured from osteoarthritic patients. Also, this growth factor was shown to bind to CCN family protein 2 (CCN2), which regenerates damaged articular cartilage and counteracts osteoarthritis (OA) in an animal model. However, the pathophysiological role of FGF-1 in cartilage has not been well investigated. In this study, we evaluated the effects of FGF-1 in vitro and its production in vivo by use of an OA model. Treatment of human chondrocytic cells with FGF-1 resulted in marked repression of genes for cartilaginous extracellular matrix components, whereas it strongly induced matrix metalloproteinase 13 (MMP-13), representing its catabolic effects on cartilage. Interestingly, expression of the CCN2 gene was dramatically repressed by FGF-1, which repression eventually caused the reduced production of CCN2 protein from the chondrocytic cells. The results of a reporter gene assay revealed that this repression could be ascribed, at least in part, to transcriptional regulation. In contrast, the gene expression of FGF-1 was enhanced by exogenous FGF-1, indicating a positive feedback system in these cells. Of note, induction of FGF-1 was observed in the articular cartilage of a rat OA model. These results collectively indicate a pathological role of FGF-1 in OA development, which includes an insufficient cartilage regeneration response caused by CCN2 down regulation.
Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan.
Abdellatif
A
El-Seoudi
Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, Japan.
Tarek
T
Abd El Kader
Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan.
Takashi
T
Nishida
Department of Dental Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Takanori
T
Eguchi
Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, Japan.
Eriko
E
Aoyama
Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, Japan. takigawa@md.okayama-u.ac.jp.
Masaharu
M
Takigawa
Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan. kubota1@md.okayama-u.ac.jp.|Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, Japan. kubota1@md.okayama-u.ac.jp.
Satoshi
S
Kubota
CCN2; Cartilage; Chondrocytes; FGF-1; Osteoarthritis