Abstract
Fibroblastic growth factor receptor 1 (FGFR1) signaling pathways are implicated in the regulation of FGF-23 gene transcription, but the molecular pathways remain poorly defined. We used low molecular weight (LMW, 18 kDa) FGF-2 and high molecular weight (HMW) FGF-2 isoforms, which, respectively, activate cell surface FGF receptors and intranuclear FGFR1, to determine the roles of membrane FGFRs and integrative nuclear FGFR1 signaling (INFS) in the regulation of FGF-23 gene transcription in osteoblasts. We found that LMW-FGF-2 induced NFAT and Ets1 binding to conserved cis-elements in the proximal FGF-23 promoter and stimulated FGF-23 promoter activity through PLCγ/calcineurin/NFAT and MAPK pathways in SaOS-2 and MC3T3-E1 osteoblasts. In contrast, HMW-FGF-2 stimulated FGF-23 promoter activity in osteoblasts through a cAMP-dependent binding of FGFR1 and cAMP-response element-binding protein (CREB) to a conserved cAMP response element (CRE) contiguous with the NFAT binding site in the FGF-23 promoter. Mutagenesis of the NFAT and CRE binding sites, respectively, inhibited the effects of LMW-FGF-2 and HMW-FGF-23 to stimulate FGF-23 promoter activity. FGF-2 activation of both membrane FGFRs and INFS-dependent FGFR1 pathways may provide a means to integrate systemic and local regulation of FGF-23 transcription under diverse physiological and pathological conditions.
Highlights
Mechanisms whereby local bone-derived factors regulate FGF-23 are unclear
Our studies show that low molecular weight (LMW)-FGF-2 and high molecular weight (HMW)-FGF-2 activate the FGF-23 promoter in osteoblasts through the respective FGFR membrane and integrative nuclear FGFR1 signaling (INFS) pathways (Fig. 7)
LWM-FGF-2 activation of membrane FGFRs is coupled to FGF-23 gene transcription through activation of PLC␥-dependent NFAT and MAPK-dependent signaling leading to binding of phosphorylated NFAT and ETS-1 to binding sites in the proximal FGF-23 promoter
Summary
Results: Low and high molecular weight FGF-2 stimulated FGF-23 promoter activity in osteoblasts through membrane FGFRmediated PLC␥ and MAPK activation of NFAT and Ets and integrative nuclear FGFR1 signaling involving cAMP/CBP/CREB signaling pathways, respectively. We used low molecular weight (LMW, 18 kDa) FGF-2 and high molecular weight (HMW) FGF-2 isoforms, which, respectively, activate cell surface FGF receptors and intranuclear FGFR1, to determine the roles of membrane FGFRs and integrative nuclear FGFR1 signaling (INFS) in the regulation of FGF-23 gene transcription in osteoblasts. FGF-2 activation of both membrane FGFRs and INFS-dependent FGFR1 pathways may provide a means to integrate systemic and local regulation of FGF-23 transcription under diverse physiological and pathological conditions. HMW-FGF-2 isoforms have an N-terminal nuclear localization sequence (NLS) that leads to nuclear localization and activation of intracellular FGFR1/CBP/CREB signaling pathways ( called integrative FGFR1 nuclear pathway or INFS) [36]. To understand the roles of membrane FGFR1 and INFS in regulating FGF-23 transcription, we examined the effects LMW-FGF-2 and HMW-FGF-2 on FGF-23 transcription in osteoblasts cell lines
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