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Enhancement of Fibronectin Fibrillogenesis and Bone Formation by Basic Fibroblast Growth Factor via Protein Kinase C-Dependent Pathway in Rat Osteoblasts

Departments of Pharmacology (C.-H.T., W.-M.F.), Orthopedics (R.-S.Y., T.-H.H.), and Toxicology (S.-H.L.), College of Medicine, National Taiwan University, Taipei, Taiwan

Fibronectin (Fn) is involved in early stages of bone formation and basic fibroblast growth factor (bFGF) is an important factor regulating osteogenesis. We here found that bFGF enhanced extracellular assembly from either endogenously released or exogenously applied soluble Fn in primary cultured osteoblasts. bFGF increased protein levels of Fn using Western blotting analysis. Protein kinase C (PKC) inhibitors such as H7, 3-[1-[3-(amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3-yl)maleimide (Bisindolylmaleimide IX), methanesulfonate (Ro 318220,) or 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c] carbazole (Gö 6976) antagonized the increase of Fn protein by bFGF. Treatment of osteoblasts with bFGF increased membrane translocation of various isoforms of PKC, including , , , and . However, treatment with antisense of various PKC isoforms demonstrated that and isozymes play important roles in the enhancement action of bFGF on Fn assembly. Down-regulation of PKC by prolonged treatment with 1 µM 12-O-tetradecanoylphorbol-13 acetate for 24 h inhibited the potentiating action of bFGF. It has been reported that 51 integrin is related to Fn fibrillogenesis, and immunocytochemistry showed that bFGF treatment increased the clustering of 5 integrins. Flow cytometry analysis demonstrated that bFGF increased cell surface expression of 5 and 1 integrins and PKC inhibitors antagonized the increase by bFGF. Local administration of bFGF into the metaphysis of the tibia via the implantation of a needle cannula significantly increased the protein levels of Fn in the area of trabecular spongiosa, which was inhibited by coadministration of PKC inhibitors. Furthermore, local injection of bFGF increased the bone volume of secondary spongiosa in tibia, which was significantly antagonized by PKC inhibitors. These results suggest that bFGF increased bone formation and Fn fibrillogenesis both in vitro and in vivo via PKC-dependent pathway.

Address correspondence to: Fu Wen-Mei, Department of Pharmacology, College of Medicine, National Taiwan University, 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan. E-mail: wenmei{at}ha.mc.ntu.edu.tw

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