Anabolic Actions of Fibroblast Growth Factor 2 on Bone Formation are medicated by Acting Transcription Factor 4 and by Modulation of the Wnt Signaling pathway

Date of Completion

January 2012

Keywords

Biology, Cell|Biology, Endocrinology|Health Sciences, Aging

Degree

Ph.D.

Abstract

Our previous studies showed that fibroblast growth factor 2 (FGF2) intermittent treatment stimulates osteoblast differentiation and bone formation. However, the detailed mechanism(s) is not fully defined. We hypothesize that anabolic actions of FGF2 in bone are mediated in part by activating transcription factor 4 (ATF4) and by the Wnt signaling pathway. ATF4 is essential for osteoblasts differentiation. The first aim of the study was to examine the ability of FGF2 to increase ATF4 expression in osteoblasts. We demonstrated that FGF2 positively regulates ATF4 expression in osteoblasts, suggesting that impaired osteoblast differentiation and bone formation in Fgf2-/- mice may be partially due to reduced ATF4 expression. ^ The second aim was to investigate whether ATF4 is a mediator of the impaired anabolic response to parathyroid hormone (PTH) in Fgf2-/- mice. PTH is currently the only available anabolic agent for the treatment of osteoporosis in the U.S. In vitro and in vivo data have shown that increased ATF4 expression by PTH was attenuated by FGF2 ablation, indicating that reduced ATF4 expression may result in decreased osteoblast differentiation, and possibly contribute to the impaired stimulation of PTH on bone formation in Fgf2-/- mice. ^ Wnt signaling is particularly important for bone homeostasis. The third & fourth aims were to explore modulation of the Wnt/β-Catenin signaling in osteoblasts both in the absence of endogenous FGF2 and in the presence of exogenous FGF2. We observed that FGF2 deletion results in profound changes in expression of ligand Wnt10b, receptor lipoprotein receptor-related protein 6 and β-Catenin during osteoblast differentiation. FGF2 modulation of Wnt/β-Catenin signaling may be through kinase glycogen synthase kinase-3, a negative regulator of Wnt/β-Catenin pathway as well as Dickkopf 2, which plays a role in terminal osteoblast differentiation. Addition of exogenous FGF2 promoted β-Catenin nuclear accumulation and partially rescued decreased mineralization in Fgf2-/- bone marrow stromal cell cultures. These data demonstrate a role of endogenous FGF2 in bone formation through Wnt signaling. These results will advance our understanding of cross-talk between FGF2 and Wnt/β-Catenin signaling in bone biology. Our studies may offer insights and suggest new approaches for the treatment of bone diseases with low bone formation. ^

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