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Functional diversity of fibroblast growth factors in bone formation.

Takei Y, Minamizaki T, Yoshiko Y - Int J Endocrinol (2015)

Bottom Line: This polypeptide decreases serum phosphate levels by inhibiting renal phosphate reabsorption and vitamin D3 activation, resulting in mineralization defects in the bone.Thus, FGFs are involved in the positive and negative regulation of bone formation.In this review, we focus on the reciprocal roles of FGFs in bone formation in relation to their local versus systemic effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Calcified Tissue Biology, Hiroshima University Institute of Biomedical & Health Sciences, 1-2-3 Kasumi Minami-ku, Hiroshima 734-8553, Japan.

ABSTRACT
The functional significance of fibroblast growth factor (FGF) signaling in bone formation has been demonstrated through genetic loss-of-function and gain-of-function approaches. FGFs, comprising 22 family members, are classified into three subfamilies: canonical, hormone-like, and intracellular. The former two subfamilies activate their signaling pathways through FGF receptors (FGFRs). Currently, intracellular FGFs appear to be primarily involved in the nervous system. Canonical FGFs such as FGF2 play significant roles in bone formation, and precise spatiotemporal control of FGFs and FGFRs at the transcriptional and posttranscriptional levels may allow for the functional diversity of FGFs during bone formation. Recently, several research groups, including ours, have shown that FGF23, a member of the hormone-like FGF subfamily, is primarily expressed in osteocytes/osteoblasts. This polypeptide decreases serum phosphate levels by inhibiting renal phosphate reabsorption and vitamin D3 activation, resulting in mineralization defects in the bone. Thus, FGFs are involved in the positive and negative regulation of bone formation. In this review, we focus on the reciprocal roles of FGFs in bone formation in relation to their local versus systemic effects.

No MeSH data available.


Related in: MedlinePlus

1,25(OH)2D3 increases Fgf9 and Fgf23 gene expression at late development stages in rat calvaria cell cultures. Rat calvaria cells were obtained as shown in Figure 2. At day 11, nodule-forming cells were stripped by collagenase and replated (subcultures). Four days later, osteoblast subcultures were pretreated with or without actinomycin D (ActD) or cycloheximide (CHX), followed by incubation with 1 nM 1,25(OH)2D3 for 6 h. See the above mentioned for qPCR. Data represent means ± S.D. n = 3. Statistical significance of differences was analyzed with one-way or two-way analysis of variance (ANOVA) with repeated measures, followed by Tukey's multiple comparison test. **P < 0.01 versus vehicle alone; ##P < 0.01 versus 1,25(OH)2D3 alone.
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fig3: 1,25(OH)2D3 increases Fgf9 and Fgf23 gene expression at late development stages in rat calvaria cell cultures. Rat calvaria cells were obtained as shown in Figure 2. At day 11, nodule-forming cells were stripped by collagenase and replated (subcultures). Four days later, osteoblast subcultures were pretreated with or without actinomycin D (ActD) or cycloheximide (CHX), followed by incubation with 1 nM 1,25(OH)2D3 for 6 h. See the above mentioned for qPCR. Data represent means ± S.D. n = 3. Statistical significance of differences was analyzed with one-way or two-way analysis of variance (ANOVA) with repeated measures, followed by Tukey's multiple comparison test. **P < 0.01 versus vehicle alone; ##P < 0.01 versus 1,25(OH)2D3 alone.

Mentions: Compared with FGF2, other canonical FGFs have not been studied in detail (Table 1). Although Fgf1 expression was not obvious in our model, its transcript appears to act in the same manner as FGF2 [30]. Intravenous administration of FGF1 increases bone formation of femoral diaphysis in normal rats [30] and tibial metaphysis in ovariectomized rats [24]. However, Fgf1−/− mice do not display any gross phenotypic defects [31]. Because deficiency of FGF1 in mice exacerbated high-fat diet-induced diabetic phenotypes, such as insulin resistance and defects in adipose remodeling in gonadal white adipose tissue, FGF1, may directly and/or indirectly act on bone. FGF4 is more specific to mesenchymal cells, but its subcutaneous injections increase trabecular bone mineral density in the mouse femur [32]. Much less is known about the roles of FGF6 [33], FGF7 [34], and FGF8 [35] in bone; the expression of Fgf7 but not of Fgf6 and Fgf8 is detected in our calvaria cell model, and FGF6 shows catabolic effects on osteoblastic cells, but others have anabolic function in vitro. Histological evidence for chondrogenesis with the upregulation of the Sox9 and Col2a1 genes is seen in cranial mesenchymal cells of transgenic mice overexpressing FGF9, suggesting that FGF9 converts intramembranous ossification to endochondral ossification [36]. FGF9 also shows supportive effects on FGF2-dependent trabecular bone formation [37]. Among Fgfs expressed in our model, Fgf9 is abundant during the late developmental stages, along with Fgf23 levels (Figure 2). Notably, both mRNA levels are upregulated by 1,25(OH)2D3, while only Fgf9 levels are suppressed by pretreatment of cycloheximide, a protein synthesis inhibitor, as well as the transcriptional inhibitor actinomycin D (Figure 3). Thus, 1,25(OH)2D3-dependent expression of Fgf9 but not Fgf23 may result from de novo protein synthesis. Additional role(s) and the precise regulatory mechanism of FGF9 in osteoblast functions remain to be elucidated. Functional anomalies in FGF10 signals may be involved in craniosynostosis [38], but there are no obvious effects of FGF10 in our rat (unpublished data) and mouse calvaria cells [39]. Treatment of mouse calvaria cells with FGF18 promotes proliferation and suppresses differentiation and matrix mineralization [39]. In Fgf18−/− mouse embryos, calvaria cell proliferation and bone mineralization and kyphosis are observed in the cervical and upper thoracic spine [40]. Together with the observation that treatment of mouse calvaria cells with FGF18 increases proliferation and decreases matrix mineralization [39], the effects of this polypeptide on bone formation appear to be similar to those of FGF2.


Functional diversity of fibroblast growth factors in bone formation.

Takei Y, Minamizaki T, Yoshiko Y - Int J Endocrinol (2015)

1,25(OH)2D3 increases Fgf9 and Fgf23 gene expression at late development stages in rat calvaria cell cultures. Rat calvaria cells were obtained as shown in Figure 2. At day 11, nodule-forming cells were stripped by collagenase and replated (subcultures). Four days later, osteoblast subcultures were pretreated with or without actinomycin D (ActD) or cycloheximide (CHX), followed by incubation with 1 nM 1,25(OH)2D3 for 6 h. See the above mentioned for qPCR. Data represent means ± S.D. n = 3. Statistical significance of differences was analyzed with one-way or two-way analysis of variance (ANOVA) with repeated measures, followed by Tukey's multiple comparison test. **P < 0.01 versus vehicle alone; ##P < 0.01 versus 1,25(OH)2D3 alone.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig3: 1,25(OH)2D3 increases Fgf9 and Fgf23 gene expression at late development stages in rat calvaria cell cultures. Rat calvaria cells were obtained as shown in Figure 2. At day 11, nodule-forming cells were stripped by collagenase and replated (subcultures). Four days later, osteoblast subcultures were pretreated with or without actinomycin D (ActD) or cycloheximide (CHX), followed by incubation with 1 nM 1,25(OH)2D3 for 6 h. See the above mentioned for qPCR. Data represent means ± S.D. n = 3. Statistical significance of differences was analyzed with one-way or two-way analysis of variance (ANOVA) with repeated measures, followed by Tukey's multiple comparison test. **P < 0.01 versus vehicle alone; ##P < 0.01 versus 1,25(OH)2D3 alone.
Mentions: Compared with FGF2, other canonical FGFs have not been studied in detail (Table 1). Although Fgf1 expression was not obvious in our model, its transcript appears to act in the same manner as FGF2 [30]. Intravenous administration of FGF1 increases bone formation of femoral diaphysis in normal rats [30] and tibial metaphysis in ovariectomized rats [24]. However, Fgf1−/− mice do not display any gross phenotypic defects [31]. Because deficiency of FGF1 in mice exacerbated high-fat diet-induced diabetic phenotypes, such as insulin resistance and defects in adipose remodeling in gonadal white adipose tissue, FGF1, may directly and/or indirectly act on bone. FGF4 is more specific to mesenchymal cells, but its subcutaneous injections increase trabecular bone mineral density in the mouse femur [32]. Much less is known about the roles of FGF6 [33], FGF7 [34], and FGF8 [35] in bone; the expression of Fgf7 but not of Fgf6 and Fgf8 is detected in our calvaria cell model, and FGF6 shows catabolic effects on osteoblastic cells, but others have anabolic function in vitro. Histological evidence for chondrogenesis with the upregulation of the Sox9 and Col2a1 genes is seen in cranial mesenchymal cells of transgenic mice overexpressing FGF9, suggesting that FGF9 converts intramembranous ossification to endochondral ossification [36]. FGF9 also shows supportive effects on FGF2-dependent trabecular bone formation [37]. Among Fgfs expressed in our model, Fgf9 is abundant during the late developmental stages, along with Fgf23 levels (Figure 2). Notably, both mRNA levels are upregulated by 1,25(OH)2D3, while only Fgf9 levels are suppressed by pretreatment of cycloheximide, a protein synthesis inhibitor, as well as the transcriptional inhibitor actinomycin D (Figure 3). Thus, 1,25(OH)2D3-dependent expression of Fgf9 but not Fgf23 may result from de novo protein synthesis. Additional role(s) and the precise regulatory mechanism of FGF9 in osteoblast functions remain to be elucidated. Functional anomalies in FGF10 signals may be involved in craniosynostosis [38], but there are no obvious effects of FGF10 in our rat (unpublished data) and mouse calvaria cells [39]. Treatment of mouse calvaria cells with FGF18 promotes proliferation and suppresses differentiation and matrix mineralization [39]. In Fgf18−/− mouse embryos, calvaria cell proliferation and bone mineralization and kyphosis are observed in the cervical and upper thoracic spine [40]. Together with the observation that treatment of mouse calvaria cells with FGF18 increases proliferation and decreases matrix mineralization [39], the effects of this polypeptide on bone formation appear to be similar to those of FGF2.

Bottom Line: This polypeptide decreases serum phosphate levels by inhibiting renal phosphate reabsorption and vitamin D3 activation, resulting in mineralization defects in the bone.Thus, FGFs are involved in the positive and negative regulation of bone formation.In this review, we focus on the reciprocal roles of FGFs in bone formation in relation to their local versus systemic effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Calcified Tissue Biology, Hiroshima University Institute of Biomedical & Health Sciences, 1-2-3 Kasumi Minami-ku, Hiroshima 734-8553, Japan.

ABSTRACT
The functional significance of fibroblast growth factor (FGF) signaling in bone formation has been demonstrated through genetic loss-of-function and gain-of-function approaches. FGFs, comprising 22 family members, are classified into three subfamilies: canonical, hormone-like, and intracellular. The former two subfamilies activate their signaling pathways through FGF receptors (FGFRs). Currently, intracellular FGFs appear to be primarily involved in the nervous system. Canonical FGFs such as FGF2 play significant roles in bone formation, and precise spatiotemporal control of FGFs and FGFRs at the transcriptional and posttranscriptional levels may allow for the functional diversity of FGFs during bone formation. Recently, several research groups, including ours, have shown that FGF23, a member of the hormone-like FGF subfamily, is primarily expressed in osteocytes/osteoblasts. This polypeptide decreases serum phosphate levels by inhibiting renal phosphate reabsorption and vitamin D3 activation, resulting in mineralization defects in the bone. Thus, FGFs are involved in the positive and negative regulation of bone formation. In this review, we focus on the reciprocal roles of FGFs in bone formation in relation to their local versus systemic effects.

No MeSH data available.


Related in: MedlinePlus