Optimization of Fibroblast Growth Factor-1 as an Anabolic Agent for Osteoporosis

摘要

Osteoporosis is a disease that afflicts 200 million people worldwide, and that number is expected to increase significantly in the future. Currently, all approved osteoporosis drugs prevent bone loss by interfering with osteoclast function. The greatest therapeutic challenge in the field of osteoporosis is the identification of agents that promote significant bone formation. Fibroblast growth factor 1 (FGF-1) has been shown to be a potent bone anabolic peptide. The goal of this proposal has been to develop mutant forms of FGF- 1 that maintain their bone anabolic potential while at the same time reducing its toxic effects (primarily epithelial hyperproliferation) upon systemic administration. Several mutant FGF proteins were developed and their bone anabolic potential compared. Among these Arg 136 % Lys mutant was the most osteoinductive followed by Cys- free > FGF-1 > FGF-HBGAM chimera. Furthermore, we demonstrate that injection of FGF- 1 directly into the marrow cavity induces new bone formation suggesting the possibility of local delivery as a strategy to specifically increase the density of bone that are at risk of fracture.