Basic fibroblast growth factor has rapid bone anabolic effects in ovariectomized rats.

Abstract

Basic fibroblast growth factor (bFGF) has a strong bone anabolic effect in intact and ovariectomized (OVX) rats treated for 7-14 days. Other growth factors such as IGF-I and TGF-beta have been implicated as potential mediators for this effect. The purpose of this study was to examine the early effects of bFGF therapy, in vivo, on bone formation and gene expression in OVX rats in order to determine whether upregulation of gene expression for IGF-I and/or TGF-beta precedes or coincides with the stimulatory effects of bFGF on bone formation. At 3 months of age, Sprague Dawley rats were OVX or sham-operated (SHAM), then maintained untreated for 3 months. One group of baseline OVX rats (BSL OVX) and BSL SHAM rats were then killed. Additional OVX groups were treated IV with bFGF at a daily dose of 200 microg/kg and killed at 1-7 and 10 days. Another group of OVX rats was treated IV with vehicle daily for 10 days, then killed. Lumbar vertebrae were processed for cancellous bone histomorphometry or RNA isolation. Ovariectomy induced increased cancellous bone turnover and a significant decrease in vertebral bone mass. Treatment of OVX rats with bFGF resulted in a significant increase in bone formation. As early as 24 h after bFGF treatment of OVX rats, osteoblast surface, osteoid surface, and osteoid volume were more than double those in BSL OVX rats and continued to increase with time. These variables were also significantly higher in bFGF-treated OVX rats at 10 days compared with vehicle-treated OVX rats. Gene expression for IGF-I was not different between BSL OVX rats and bFGF-treated OVX rats at 1 day, but was significantly higher by approximately 50% in OVX rats treated with bFGF for 2 and 7 days, and was also significantly higher by nearly 75% in OVX rats treated for 10 days compared with OVX rats treated with vehicle. Gene expression for TGF-beta1 was unchanged at early times and only significantly upregulated by a relatively modest 30% in OVX rats treated with bFGF for 10 days. The results indicate that the bone anabolic effects of bFGF in OVX rats begin as early as 24 h following the initial treatment, and increase with time. These early stages of the strong stimulatory effect of bFGF on bone formation were not associated with a large upregulation of gene expression for IGF-I and TGF-beta. The rapid increase in osteoblast surface in bFGF-treated OVX rats suggests that the growth factor induces conversion of bone lining cells to osteoblasts.