Fibroblast Growth Factor-2 Isoform (Low Molecular Weight/18 kDa) Overexpression in Preosteoblast Cells Promotes Bone Regeneration in Critical Size Calvarial Defects in Male Mice

Abstract

Repair of bone defects remains a significant clinical problem. Bone morphogenetic protein 2 (BMP2) is US Food and Drug Administration-approved for fracture healing but is expensive and has associated morbidity. Studies have shown that targeted overexpression of the 18-kDa low-molecular-weight fibroblast growth factor 2 isoform (LMW) by the osteoblastic lineage of transgenic mice increased bone mass. This study tested the hypotheses that overexpression of LMW would directly enhance healing of a critical size calvarial bone defect in mice and that this overexpression would have a synergistic effect with low-dose administration of BMP2 on critical size calvarial bone defect healing. Bilateral calvarial defects were created in LMW transgenic male mice and control/vector transgenic (Vector) male mice and scaffold with or without BMP2 was placed into the defects. New bone formation was assessed by VIVA-computed tomography of live animals over a 27-week period. Radiographic and computed tomography analysis revealed that at all time points, healing of the defect was enhanced in LMW mice compared with that in Vector mice. Although the very low concentration of BMP2 did not heal the defect in Vector mice, it resulted in complete healing of the defect in LMW mice. Histomorphometric and gene analysis revealed that targeted overexpression of LMW in osteoblast precursors resulted in enhanced calvarial defect healing due to increased osteoblast activity and increased canonical Wnt signaling.

The use of bioactive factors to enhance bone regeneration: A narrative review

“…A synergistic effect of FGF‐2 and BMP‐2 has been suggested by several experimental studies (Charles et al., ; Gronowicz et al., ; Su et al., ; Xiao et al., ). As previously mentioned, adding FGF‐2 might allow to reduce the dose of BMP‐2, thus reducing the risk of the negative side effects associated to a high dosage of this growth factor, and would promote hMSCs proliferation and osteogenic differentiation (Akita, Fukui, Nakagawa, Fujii & Akino, ).…”

“…Some pre‐clinical studies have shown that combining BMP‐2 with other growth factors (Charles, Woodman, Ueno, Gronowicz & Hurley, ; Gronowicz, Jacobs, Peng, Zhu & Hurley, ; Jo, Jeong, Shin, Kang & Kim, ; Su, Xu, Sun, Gong & Zhao, ; Xiao, Ueno, Catros, Homer‐Bouthiette & Charles, ) would allow to reduce the amount of BMP‐2 delivered, thus reducing the associated side effects, such as ectopic bone formation, osteoclast activation, long‐lasting oedema formation, as well as erythema in the vicinity of the site of implantation and inappropriate adipogenesis (James, LaChaud, Shen, Asatrian & Nguyen, ; Zara, Siu, Zhang, Shen & Ngo, ), while maintaining positive regenerative outcomes.…”

“…The combination of rhBMP‐2 with other BMPs or growth factors (e.g. FGF‐2) might overcome this problem and allow to reduce the dose of rhBMP‐2 delivered (Charles et al., ; Gronowicz et al., ; Su et al., ; Xiao et al., ).…”

Isoform‐selective as opposed to complete depletion of fibroblast growth factor 2 (FGF‐2) has no major impact on survival and gene expression in SOD1G93A amyotrophic lateral sclerosis mice

“…In fact evidence exists that FGF‐2 LMW and not FGF‐2 HMW favors bone regeneration, as FGF‐2 LMW knockout leads to decreases in mineralized bone density (Xiao et al., ), whereas FGF‐2 HMW knockout benefits bone and phosphate homeostasis in vivo (Homer‐Buthiette, Doetschman, Xiao, & Hurley, ). Moreover, overexpression of FGF‐2 LMW increases bone mass by enhanced osteoblast activity (Xiao et al., ). Apart from its positive effects on bone maintenance, FGF‐2 LMW was also reported to promote inflammation and support oxidative stress in atherosclerosis (Liang, Wang, Ma, Yan, & Yang, ).…”

Deferoxamine released from poly(lactic‐co‐glycolic acid) promotes healing of osteoporotic bone defect via enhanced angiogenesis and osteogenesis

“…In addition to angiogenic effects, VEGF and FGF-2 possess stimulatory effects on osteogenic differentiation of MSCs; hence VEGF and FGF-2 accelerate bone defect healing. 66,[84][85][86][87] Besides influencing the HIF-1a signaling pathway, DFO can also activate the Wnt/b-Catenin signaling pathway, enhancing osteogenic differentiation of MSCs. 40,41 This phenomenon is confirmed by our ALP and AR staining, and upregulated mRNA expression levels of Runx-2 and osteocalcin.…”