Fibroblast growth factor-2 induces osteoblast survival through a phosphatidylinositol 3-kinase-dependent, -β-catenin-independent signaling pathway

Debiais, Françoise; Lefèvre, G.; Lemonnier, Jérôme; Mée, Sandrine Le; Lasmoles, F.; Mascarelli, Frédéric; Marie, Pierre J.

doi:10.1016/j.yexcr.2004.03.032

Cited by 77 publications

(59 citation statements)

References 57 publications

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“…One study (59) reported that FGF2 did not induce ␤-catenin nuclear accumulation, which is not consistent with our results and other reports (55)(56)(57)(58). However, those experiments used different FGF2 treatment durations, and the cell source was different whereby that study (59) used normal human neonatal calvarial osteoblastic cells immortalized by transfection with truncated SV40. Our studies using BMSCs showed that amplified Wnt/␤-catenin signaling strongly correlates with higher osteogenic differentiation, consistent with other reports (3,55).…”

Section: Expression (C) D and E ␤-Catenin Mrna (D) And ␤-Catenin Prcontrasting

confidence: 92%

“…FGF2 enhancement of ␤-catenin nuclear accumulation has also been reported in calvarial osteoblasts (55), human endothelial cells (56), neural stem cells (57), as well as in human embryonic stem cells (58). One study (59) reported that FGF2 did not induce ␤-catenin nuclear accumulation, which is not consistent with our results and other reports (55)(56)(57)(58). However, those experiments used different FGF2 treatment durations, and the cell source was different whereby that study (59) used normal human neonatal calvarial osteoblastic cells immortalized by transfection with truncated SV40.…”

Section: Expression (C) D and E ␤-Catenin Mrna (D) And ␤-Catenin Prmentioning

confidence: 86%

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Fibroblast Growth Factor 2 Stimulation of Osteoblast Differentiation and Bone Formation Is Mediated by Modulation of the Wnt Signaling Pathway

Fei

Xiao

Doetschman

et al. 2011

Journal of Biological Chemistry

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Fibroblast growth factor 2 (FGF2) positively modulates osteoblast differentiation and bone formation. However, the mechanism(s) is not fully understood. Because the Wnt canonical pathway is important for bone homeostasis, this study focuses on modulation of Wnt/␤-catenin signaling using Fgf2 Both embryonic and postnatal skeletogenesis involve mesenchymal precursor cells progressively differentiating into boneforming cells, osteoblasts (1). Osteoblast differentiation is controlled by extracellular signals, including both the FGF (2) and Wnt pathways (3).FGF2 is one member of the FGF family (2, 4). It is expressed by osteoblasts (5-7) and stored in the extracellular matrix (7). Our previous studies show that FGF2 positively regulates bone formation and osteoblast differentiation. Disruption of the Fgf2 gene resulted in significantly decreased bone mass and bone formation as revealed by histomorphometry and micro-CT (8). At the cellular level, the effects of FGF2 ablation on osteoblast phenotypes included decreased osteoblast proliferation, reduced colony-forming efficiency in Fgf2 Ϫ/Ϫ bone marrow stromal cell (BMSC) 2 cultures, and decreased alkaline phosphatase and von Kossa staining (8 -10). The osteoblast function was also confirmed in vivo: bone formation rates were significantly reduced in Fgf2 Ϫ/Ϫ mice compared with wild-type littermates (8) The decreased osteoblast differentiation in Fgf2 Ϫ/Ϫ BMSC cultures can be partially rescued by adding exogenous FGF2 in vitro (8, 9). FGF2 also stimulates in vivo bone formation (11)(12)(13)(14). Differentiation of BMSCs into the osteoblast lineage is governed by transcription factors, including runt-related transcription factor 2 (Runx2), Osterix, and activating transcription factor 4 (ATF4) (1). Decreased osteoblast differentiation might be due to reduced expression of transcription factors Runx2 (9) and ATF4 (15), which were associated with reduced bone formation in Fgf2 Ϫ/Ϫ mice. Furthermore, exogenous FGF2 was able to induce Runx2 (16) and ATF4 (15) expression. These studies suggest that FGF2 is a positive regulator of bone formation. In addition, FGF2 is required for osteoclast formation and bone resorption because FGF2 deletion results in reduced osteoclast formation and resorption both in vitro (17) and in vivo (8). The present study focused on potential mechanisms by which FGF2 regulates osteoblast differentiation and bone formation.Wnts are secreted glycoproteins with a family of 19 proteins in mammals, including Wnt3a and Wnt10b (18). Wnt10b stimulates osteogenic transcription factor Runx2, thereby promoting osteoblastogenesis and bone formation (19,20). Wnt ligands can signal through either the ␤-catenin-dependent or -independent pathways (21). The ␤-catenin-dependent Wnt pathway is well studied in osteoblasts (3). In the absence of Wnt ligands, ␤-catenin is degraded by a destruction complex which includes glycogen synthase kinase 3␤ (GSK3␤) (3,21,22). Thus, GSK3␤ is a negative regulator of the ␤-catenin/Wnt pathway. Binding of Wnt ligands to the Frizzled rec...

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Section: Expression (C) D and E ␤-Catenin Mrna (D) And ␤-Catenin Prcontrasting

confidence: 92%

Section: Expression (C) D and E ␤-Catenin Mrna (D) And ␤-Catenin Prmentioning

confidence: 86%

Fibroblast Growth Factor 2 Stimulation of Osteoblast Differentiation and Bone Formation Is Mediated by Modulation of the Wnt Signaling Pathway

Fei

Xiao

Doetschman

et al. 2011

Journal of Biological Chemistry

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“…Another functional response to FGFR signaling is modulation of cell survival. We previously showed that FGF2 has distinct effects on osteoblast survival depending on the stage of differentiation (52). Additionally, activated FGFR2 mutations were shown to increase osteoblast apoptosis in murine and human osteoblasts (51,53).…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor Receptor 2 Promotes Osteogenic Differentiation in Mesenchymal Cells via ERK1/2 and Protein Kinase C Signaling

Miraoui

Oudina

Petite

et al. 2009

Journal of Biological Chemistry

135

134

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Mesenchymal stem cells (MSCs)3 have the potential to differentiate into different lineages, including osteoblasts, chondroblasts, and adipocytes (1-7). The osteoblast differentiation program of MSCs is characterized by cell recruitment, which is followed by timely expressed genes including Runx2, alkaline phosphatase (ALP), type I collagen (ColA1), and osteocalcin (OC), which is associated with extracellular matrix mineralization (8 -10). The program of MSC osteogenic differentiation can be induced by soluble molecules such as bone morphogenetic proteins (BMPs) or Wnt proteins that activate several signaling pathways to trigger osteoblast differentiation (11-15). Although various downstream signals are known to promote osteogenic differentiation (16 -20), the molecular mechanisms that control the early stages of MSC osteoblast differentiation are not fully elucidated.Fibroblast growth factors (FGFs) play an important major role in the control of cell proliferation, differentiation, and survival in several tissues including bone (21-24). Notably, FGF2 was found to promote cell growth and osteoblast differentiation in bone marrow-derived mesenchymal cells (25,26). Consistent with an important role of FGF signaling in the control of osteoprogenitor cells, deletion of FGF2 in mice results in decreased bone marrow stromal cell osteogenic differentiation and altered bone formation (27). The actions of FGFs are highly dependent on high affinity FGF receptors (FGFRs) (28). FGF binding to FGFRs leads to receptor dimerization and phosphorylation of intrinsic tyrosine residues, which leads to activation of several signal transduction pathways including phospholipase C␥ (PLC␥), mitogen-activated protein kinases (MAPK), and phosphatidylinositol 3-kinase (PI3K) (29,30). In bone, activation of extracellular-related kinase (ERK1/2) MAPK and protein kinase C (PKC) was found to enhance osteoblast gene expression (31, 32). The important role of FGFR signaling in bone formation is highlighted by the finding that gain-of-function mutations in FGFRs results in premature cranial osteogenesis (33, 34). FGFR1 was recently shown to be an important transducer of FGF signals in proliferating osteoblasts (35). In contrast, activated FGFR2 was shown to enhance osteoblast differentiation in Apert syndromic craniosynostosis (36 -41). However, the role of FGFR2 signaling in osteogenic differentiation of mesenchymal stem cells is yet to be elucidated.In the present study, we investigated the specific role of FGFR2 signaling on osteoblast commitment and differentiation

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“…The osteoblasts can also be de-sensitized to apoptosis, notably by growth factors like FGF, TGF-j8 and others (Debiais et al, 2004, Jilka et al, 1998. The pathways can be rather direct; for example, IGFs upregulate the molecule calbindin-D28k, which binds to caspase-3, inactivating it in the process (Wernyj et al, 1999).…”

Section: Apoptosis: Regulation Of Remodelingmentioning

confidence: 99%

“…This blocks TNF-induced apoptosis in the osteoblast-lineage cells (Bellido et al, 2000). The pathway taken by FGF is less direct, involving PI3-kinase activity and promotion of the anti-apoptotic signal (Debiais et al, 2004). TGF-/3, a molecule of interest, inhibits osteoblast apoptosis by decreasing the ratio of Bax to Bcl-2 (Bu R et al 2003).…”

Section: Apoptosis: Regulation Of Remodelingmentioning

confidence: 99%

Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro

et al. 2011

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Fibroblast growth factor-2 induces osteoblast survival through a phosphatidylinositol 3-kinase-dependent, -β-catenin-independent signaling pathway

Cited by 77 publications

References 57 publications

Fibroblast Growth Factor 2 Stimulation of Osteoblast Differentiation and Bone Formation Is Mediated by Modulation of the Wnt Signaling Pathway

Fibroblast Growth Factor 2 Stimulation of Osteoblast Differentiation and Bone Formation Is Mediated by Modulation of the Wnt Signaling Pathway

Fibroblast Growth Factor Receptor 2 Promotes Osteogenic Differentiation in Mesenchymal Cells via ERK1/2 and Protein Kinase C Signaling

Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro

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