Role of FGF/FGFR signaling in skeletal development and homeostasis: learning from mouse models

Su, Nan; Jin, Min; Chen, Lin

doi:10.1038/boneres.2014.3

Cited by 214 publications

(183 citation statements)

References 262 publications

(260 reference statements)

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“…FGFR3 is a negative regulator of bone growth, and gain-offunction mutations in FGFR3 lead to chondrodysplasias with abnormal growth plates (14). In addition, FGFR3 also regulates bone mass.…”

Section: Discussionmentioning

confidence: 99%

“…FGFR3 is also expressed in mesenchymal stem cells and osteoblasts, indicating that FGFR3 mutations in these cells may directly affect bone formation (14). For example, activated mutation of FGFR3 (Y367C) in osteoblasts led to increased bone mass in mice (35).…”

mentioning

confidence: 99%

“…Fibroblast growth factor receptor 3 (FGFR3) is one of a family of four membrane-bound receptor tyrosine kinases (FGFR1-4) linked to downstream pathways including MAPK, PKC-␥, PI3K/AKT, and STAT signaling pathways (14). FGFR3 is highly expressed in chondrocytes of growth plates (15)(16)(17)(18), and is a negative regulator of endochondral bone development (4,14). Gain-of-function mutations in FGFR3 lead to chondrodysplasias including achondroplasia (ACH), hypochondroplasia (HCH), and thanatophoric dysplasia (TD).…”

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confidence: 99%

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Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis

Wen

Tang

et al. 2016

Journal of Biological Chemistry

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Edited by Xiao-Fan WangChondrogenesis can regulate bone formation. Fibroblast growth factor receptor 3, highly expressed in chondrocytes, is a negative regulator of bone growth. To investigate whether chondrocyte FGFR3 regulates osteogenesis, thereby contributing to postnatal bone formation and bone remodeling, mice with conditional knock-out of Fgfr3 in chondrocytes (mutant (MUT)) were generated. MUT mice displayed overgrowth of bone with lengthened growth plates. Bone mass of MUT mice was significantly increased at both 1 month and 4 months of age. Histological analysis showed that osteoblast number and bone formation were remarkably enhanced after deletion of Fgfr3 in chondrocytes. Chondrocyte-osteoblast co-culture assay further revealed that Fgfr3 deficiency in chondrocytes promoted differentiation and mineralization of osteoblasts by up-regulating the expressions of Ihh, Bmp2, Bmp4, Bmp7, Wnt4, and Tgf-␤1, as well as down-regulating Nog expression. In addition, osteoclastogenesis was also impaired in MUT mice with decreased number of osteoclasts lining trabecular bone, which may be related to the reduced ratio of Rankl to Opg in Fgfr3-deficient chondrocytes. This study reveals that chondrocyte FGFR3 is involved in the regulation of bone formation and bone remodeling by a paracrine mechanism.

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Section: Discussionmentioning

confidence: 99%

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Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis

Wen

Tang

et al. 2016

Journal of Biological Chemistry

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“…These transporters control the uptake and efflux of many critical ions or substrates during amelogenesis and have been determined to result in enamel abnormalities if mutated. Mutations in SLC4A4 result in pigmentation differences and a propensity to fracture (21,(42)(43)(44)(45)(46). Patients with proximal renal tubular acidosis (pRTA) caused by mutations in SLC4A4 also exhibit dental abnormalities (5,42).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA 224 Regulates Ion Transporter Expression in Ameloblasts To Coordinate Enamel Mineralization

Fan

Zhou

et al. 2015

Molecular and Cellular Biology

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Enamel mineralization is accompanied by the release of protons into the extracellular matrix, which is buffered to regulate the pH value in the local microenvironment. The present study aimed to investigate the role of microRNA 224 (miR-224) as a regulator of SLC4A4 and CFTR, encoding the key buffering ion transporters, in modulating enamel mineralization. miR-224 was significantly downregulated as ameloblasts differentiated, in parallel with upregulation of SLC4A4 and CFTR. Overexpression of miR-224 downregulated SLC4A4 and CFTR expression in cultured human epithelial cells. A microRNA luciferase assay confirmed the specific binding of miR-224 to the 3= untranslated regions (UTRs) of SLC4A4 and CFTR mRNAs, thereby inhibiting protein translation. miR-224 agomir injection in mouse neonatal incisors resulted in normal enamel length and thickness, but with disturbed organization of the prism structure and deficient crystal growth. Moreover, the enamel Ca/P ratio and microhardness were markedly reduced after miR-224 agomir administration. These results demonstrate that miR-224 plays a pivotal role in fine tuning enamel mineralization by modulating SLC4A4 and CFTR to maintain pH homeostasis and support enamel mineralization.

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“…(10) The effect of FGFs on osteoclasts suggests that FGF receptors (FGFRs) play important roles in the regulation of osteoclast formation and function. FGFRs are membrane-bound receptor tyrosine kinases, which can activate multiple pathways including MAPK, PLC-g, PI-3K/AKT, and STAT signaling pathways, (11) and others. FGFR1 is expressed in osteoclasts, (6) and we found that specific deletion of Fgfr1 in osteoclasts leads to increased bone mass with decreased osteoclast number and activity.…”

Section: Introductionmentioning

confidence: 99%

Deletion of FGFR3 in Osteoclast Lineage Cells Results in Increased Bone Mass in Mice by Inhibiting Osteoclastic Bone Resorption

Tang

et al. 2016

Journal of Bone and Mineral Research

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Fibroblast growth factor receptor 3 (FGFR3) participates in bone remodeling. Both Fgfr3 global knockout and activated mice showed decreased bone mass with increased osteoclast formation or bone resorption activity. To clarify the direct effect of FGFR3 on osteoclasts, we specifically deleted Fgfr3 in osteoclast lineage cells. Adult mice with Fgfr3 deficiency in osteoclast lineage cells (mutant [MUT]) showed increased bone mass. In a drilled-hole defect model, the bone remodeling of the holed area in cortical bone was also impaired with delayed resorption of residual woven bone in MUT mice. In vitro assay demonstrated that there was no significant difference between the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts derived from wild-type and Fgfr3-deficient bone marrow monocytes, suggesting that FGFR3 had no remarkable effect on osteoclast formation. The bone resorption activity of Fgfr3-deficient osteoclasts was markedly decreased accompanying with downregulated expressions of Trap, Ctsk, and Mmp 9. The upregulated activity of osteoclastic bone resorption by FGF2 in vitro was also impaired in Fgfr3-deficient osteoclasts, indicating that FGFR3 may participate in the regulation of bone resorption activity of osteoclasts by FGF2. Reduced adhesion but not migration in osteoclasts with Fgfr3 deficiency may be responsible for the impaired bone resorption activity. Our study for the first time genetically shows the direct positive regulation of FGFR3 on osteoclastic bone resorption.

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Role of FGF/FGFR signaling in skeletal development and homeostasis: learning from mouse models

Cited by 214 publications

References 262 publications

Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis

Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis

MicroRNA 224 Regulates Ion Transporter Expression in Ameloblasts To Coordinate Enamel Mineralization

Deletion of FGFR3 in Osteoclast Lineage Cells Results in Increased Bone Mass in Mice by Inhibiting Osteoclastic Bone Resorption

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