Fibroblast growth factor signaling in skeletal development and disease

Ornitz, David M.; Marie, Pierre J.

doi:10.1101/gad.266551.115

Cited by 305 publications

(299 citation statements)

References 345 publications

(430 reference statements)

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“…The mineralized cartilage elements in growth plates are finally invaded by blood vessels accompanied by osteoclasts and osteoblasts, and then replaced by bone (1). FGFR3 is essential for chondrocyte hypertrophy (52). In this study, mice with deletion of Fgfr3 in chondrocytes showed an elongated hypertrophic zone with an increased number of hypertrophic chondrocytes in growth plates, which may be responsible for the increased bone volume of the primary spongiosa.…”

Section: Discussionmentioning

confidence: 81%

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: 81%

Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis

Wen

Tang

et al. 2016

Journal of Biological Chemistry

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“…Loss of function of FGFR3, either globally or specifically in chondrocytes, leads to skeletal overgrowth in mice, sheep and humans (Beever et al, 2006;Colvin et al, 1996;Deng et al, 1996;Makrythanasis et al, 2014;Ornitz and Marie, 2015;Toydemir et al, 2006;Zhou et al, 2015). The inhibitory activity of FGFR3 on growth plate chondrocytes explains the pathogenic consequences of gain-of-function mutations in FGFR3 in suppressing pre-pubertal skeletal growth in achondroplasia and related chondrodysplastic disorders (Laederich and Horton, 2012;Naski et al, 1998Naski et al, , 1996.…”

Section: Introductionmentioning

confidence: 99%

“…Fgfr3 is expressed in proliferating and prehypertrophic chondrocytes and functions to inhibit postnatal chondrogenesis (Chen et al, 2001;Havens et al, 2008;Naski et al, 1998;Ornitz and Marie, 2015;Su et al, 2014). Loss of function of FGFR3, either globally or specifically in chondrocytes, leads to skeletal overgrowth in mice, sheep and humans (Beever et al, 2006;Colvin et al, 1996;Deng et al, 1996;Makrythanasis et al, 2014;Ornitz and Marie, 2015;Toydemir et al, 2006;Zhou et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth

Karuppaiah

Lim

et al. 2016

Development

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Fibroblast growth factor (FGF) signaling is important for skeletal development; however, cell-specific functions, redundancy and feedback mechanisms regulating bone growth are poorly understood. FGF receptors 1 and 2 (Fgfr1 and Fgfr2) are both expressed in the osteoprogenitor lineage. Double conditional knockout mice, in which both receptors were inactivated using an osteoprogenitor-specific Cre driver, appeared normal at birth; however, these mice showed severe postnatal growth defects that include an ∼50% reduction in body weight and bone mass, and impaired longitudinal bone growth. Histological analysis showed reduced cortical and trabecular bone, suggesting cellautonomous functions of FGF signaling during postnatal bone formation. Surprisingly, the double conditional knockout mice also showed growth plate defects and an arrest in chondrocyte proliferation. We provide genetic evidence of a non-cell-autonomous feedback pathway regulating Fgf9, Fgf18 and Pthlh expression, which led to increased expression and signaling of Fgfr3 in growth plate chondrocytes and suppression of chondrocyte proliferation. These observations show that FGF signaling in the osteoprogenitor lineage is obligately coupled to chondrocyte proliferation and the regulation of longitudinal bone growth.

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“…(8) Studies also showed that FGF6 increases the formation and resorbing activity of primary mature osteoclasts in vitro, (9) whereas FGF8a inhibits osteoclastogenesis, but does not affect osteoclast function. (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.…”

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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Fibroblast growth factor signaling in skeletal development and disease

Cited by 305 publications

References 345 publications

Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis

Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis

FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth

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

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