Stimulation of bone formation by intraosseous application of recombinant basic fibroblast growth factor in normal and ovariectomized rabbits

Abstract

The effect on intraosseous bone formation of a single local injection of recombinant human basic fibroblast growth factor into the distal femur was examined in normal and ovariectomized rabbits. In normal rabbits, basic fibroblast growth factor increased bone mineral density around the injected site in a dose-dependent manner at 4 weeks, with significant effects at concentrations of 400 micrograms and greater. Doses of 400 and 1,600 micrograms of basic fibroblast growth factor increased bone mineral density by 8 and 9%, respectively, compared with the opposite control femur. Histological examination showed that basic fibroblast growth factor (400 micrograms) induced the proliferation or recruitment of undifferentiated mesenchymal cells around the existing trabeculae at 3 days after the injection. For the first 2 weeks, osteoid formation was strongly stimulated, and this was followed by mineral apposition for another 2 weeks, at which time the femurs were harvested. Consequently, basic fibroblast growth factor stimulated intraosseous bone formation at 4 weeks. We speculate that the direct action of basic fibroblast growth factor on bone formation may be to stimulate proliferation or recruitment of minimally differentiated mesenchymal cells and to initiate the cascade of events in later stages of bone formation. In ovariectomized rabbits, basic fibroblast growth factor (400 micrograms) also increased bone mineral density, histomorphometrical bone formation markers, and trabecular connectivity to levels similar to those in rabbits who had received sham operations.

Local application of recombinant human fibroblast growth factor‐2 on bone repair: A dose–escalation prospective trial on patients with osteotomy

“…Based on the evidence of extensive studies using various animal models, [6][7][8][9][10][11][12][13][14][15] this study for the first time showed clinical evidence that rhFGF-2 in gelatin hydrogel accelerated radiographic bone union of the closing wedge high tibial osteotomy. Because most osteotomies can heal only with appropriate fixations, and in fact, all patients even of the low dosage group eventually achieved radiographic bone union in the present study, the rhFGF-2 application may not have yielded bone union by preventing nonunion, but just accelerated bone union.…”

“…In fact, previous animal studies demonstrated that a single injection of FGF-2 enhanced the proliferation of chondroprogenitor cells in fracture callus, causing the formation of a larger cartilage, but did not directly affect maturation of chondrocytes or replacement of the cartilage by osseous tissue. 7,14,23 Furthermore, expressions of FGF-2, FGF-1, and their principal receptor FGFR1 have been identified mainly at the early stage of fracture healing. 1,[24][25][26] In addition to its mitogenic action on immature mesenchymal cells, FGF-2 may induce other anabolic factors such as prostaglandins, transforming growth factor (TGF)-b and bone morphogenetic proteins (BMPs), which may compose a serial cascade of bone formation.…”

“…[6][7][8][9][10][11][12][13][14][15] A single local application of FGF-2 facilitated the healing of bone fracture and segmental bone defect in normal and diabetic rats, rabbits, dogs, and monkeys; [6][7][8][9][10][11][12] stimulated bone formation in callotasis bone lengthening in rabbits; 13 and increased bone mass intraosseously in normal and ovariectomized rats and rabbits. 14 In addition, a daily systemic administration of FGF-2 facilitated endosteal bone formation. 15 Regarding the delivery system for clinical use, previous animal studies have revealed that FGF-2 exerted the most potent anabolic activity when a synthetic bioabsorbable hydrogel prepared through glutaraldehyde crosslinking of gelatin was used as the carrier.…”

Fibroblast Growth Factor (FGF)-2 Directly Stimulates Mature Osteoclast Function through Activation of FGF Receptor 1 and p42/p44 MAP Kinase

“…In bone tissues, FGF-2 is produced by cells of osteoblastic lineage, is accumulated in bone matrix, and acts as an autocrine/paracrine factor for bone cells (6 -10). We and others have reported that the exogenous application of FGF-2 has stimulatory effects on bone formation in several in vivo models as a pharmacological action of FGF-2 (11)(12)(13)(14)(15)(16)(17). On the other hand, in vitro studies revealed that high concentrations of FGF-2 (10 Ϫ9 -10 Ϫ8 M) stimulated osteoclastogenesis in bone marrow culture (18) and bone resorption in bone organ cultures (19,20).…”

Expression of bone morphogenetic protein 2 and fibroblast growth factor 2 during bone regeneration using different implant materials as an onlay bone graft in rabbit mandibles

“…Recent reports have shown that the addition of exogenous FGF-2 to a fracture site or bone defect during the early healing stage accelerates fracture repair and bone formation 8 . However, no experimental studies have been performed to investigate the expression of FGF-2 during bone regeneration.…”