Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3

Development ◽  
1998 ◽  
Vol 125 (24) ◽  
pp. 4977-4988 ◽  
Author(s):  
M.C. Naski ◽  
J.S. Colvin ◽  
J.D. Coffin ◽  
D.M. Ornitz
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Signaling Pathway ◽  
Growth Plate ◽  
Bone Growth ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Growth Plate Cartilage ◽  
Bmp4 Expression

Fibroblast growth factor receptor 3 (FGFR3) is a key regulator of skeletal growth and activating mutations in Fgfr3 cause achondroplasia, the most common genetic form of dwarfism in humans. Little is known about the mechanism by which FGFR3 inhibits bone growth and how FGFR3 signaling interacts with other signaling pathways that regulate endochondral ossification. To understand these mechanisms, we targeted the expression of an activated FGFR3 to growth plate cartilage in mice using regulatory elements from the collagen II gene. As with humans carrying the achondroplasia mutation, the resulting transgenic mice are dwarfed, with axial, appendicular and craniofacial skeletal hypoplasia. We found that FGFR3 inhibited endochondral bone growth by markedly inhibiting chondrocyte proliferation and by slowing chondrocyte differentiation. Significantly, FGFR3 downregulated the Indian hedgehog (Ihh) signaling pathway and Bmp4 expression in both growth plate chondrocytes and in the perichondrium. Conversely, Bmp4 expression is upregulated in the perichondrium of Fgfr3−/− mice. These data support a model in which Fgfr3 is an upstream negative regulator of the hedgehog (Hh) signaling pathway. Additionally, Fgfr3 may coordinate the growth and differentiation of chondrocytes with the growth and differentiation of osteoprogenitor cells by simultaneously modulating Bmp4 and patched expression in both growth plate cartilage and in the perichondrium.

Crouzon’s syndrome: a new surgical approach

2019 ◽  
Vol 7 (2) ◽  
pp. 18
Author(s):  
Dr. Madhumati Singh ◽  
Dr. Kishore Felix ◽  
Dr. Anjan Kumar Shah
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Bone Growth ◽  
Fibroblast Growth Factor Receptor ◽  
Genetic Disorder ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Feeding Problems ◽  
Facial Region ◽  
Crouzon's Syndrome

Crouzon’s syndrome is a rare genetic disorder characterized by distinctive malformations of the skull and facial region, premature cranial suture closure is the most common skull abnormality, optic disc edema and proptosis are among the most common ocular findings. It is a genetic disorder of gene FGFR-2 (Fibroblast Growth Factor Receptor-2) in 95% of cases, and in 5% of cases, FGFR-3 (Fibroblast Growth Factor Receptor-3) mutation occurs.Once a suture becomes fused, growth perpendicular to that suture becomes restricted and the fused bones act as a single body structure. Compensatory growth occurs at the remaining open sutures to allow continued brain growth, resulting in abnormal bone growth and producing facial deformities.In the new born child, some potential problems that may need to be addressed include respiratory difficulties, feeding problems, neurologic complications such as hydrocephalus and the potential risk of developmental delay.We represent a literature review and a rare case of Crouzon’s Syndrome, who wanted facial correction to be done at the age of 24years. We planned two stage surgical procedure, for correction of facial deformity. 

scholarly journals Chimeras of the native form or achondroplasia mutant (G375C) of human fibroblast growth factor receptor 3 induce ligand-dependent differentiation of PC12 cells.

1997 ◽  
Vol 17 (7) ◽  
pp. 4169-4177 ◽  
Author(s):  
L M Thompson ◽  
S Raffioni ◽  
J J Wasmuth ◽  
R A Bradshaw
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Pc12 Cells ◽  
Human Fibroblast ◽  
Bone Growth ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Extracellular Domain ◽  
Platelet Derived Growth Factor ◽  
Fibroblast Growth

Mutations in the gene for human fibroblast growth factor receptor 3 (hFGFR3) cause a variety of skeletal dysplasias, including the most common genetic form of dwarfism, achondroplasia (ACH). Evidence indicates that these phenotypes are not due to simple haploinsufficiency of FGFR3 but are more likely related to a role in negatively regulating skeletal growth. The effects of one of these mutations on FGFR3 signaling were examined by constructing chimeric receptors composed of the extracellular domain of human platelet-derived growth factor receptor beta (hPDGFR beta) and the transmembrane and intracellular domains of hFGFR3 or of an ACH (G375C) mutant. Following stable transfection in PC12 cells, which lack platelet-derived growth factor (PDGF) receptors, all clonal cell lines, with either type of chimera, showed strong neurite outgrowth in the presence of PDGF but not in its absence. Antiphosphotyrosine immunoblots showed ligand-dependent autophosphorylation, and both receptor types stimulated strong phosphorylation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase, an event associated with the differentiative response of these cells. In addition, ligand-dependent phosphorylation of phospholipase Cgamma and Shc was also observed. All of these responses were comparable to those observed from ligand activation, such as by nerve growth factor, of the native PC12 cells used to prepare the stable transfectants. The cells with the chimera bearing the ACH mutation were more rapidly responsive to ligand with less sustained MAPK activation, indicative of a preactivated or primed condition and consistent with the view that these mutations weaken ligand control of FGFR3 function. However, the full effect of the mutation likely depends in part on structural features of the extracellular domain. Although FGFR3 has been suggested to act as a negative regulator of long-bone growth in chrondrocytes, it produces differentiative signals similar to those of FGFR1, to which only positive effects have been ascribed, in PC12 cells. Therefore, its regulatory effects on bone growth likely result from cellular contexts and not the induction of a unique FGFR3 signaling pathway.

scholarly journals Ligand activation leads to regulated intramembrane proteolysis of fibroblast growth factor receptor 3

2011 ◽  
Vol 22 (20) ◽  
pp. 3861-3873 ◽  
Author(s):  
Catherine R. Degnin ◽  
Melanie B. Laederich ◽  
William A. Horton
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Plate ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Fibroblast Growth ◽  
Intramembrane Proteolysis ◽  
Ligand Activation ◽  
Regulated Intramembrane Proteolysis

Fibroblast growth factor receptor 3 (FGFR3) is a major negative regulator of bone growth that inhibits the proliferation and differentiation of growth plate chondrocytes. Activating mutations of its c isoform cause dwarfism in humans; somatic mutations can drive oncogenic transformation in multiple myeloma and bladder cancer. How these distinct activities arise is not clear. FGFR3 was previously shown to undergo proteolytic cleavage in the bovine rib growth plate, but this was not explored further. Here, we show that FGF1 induces regulated intramembrane proteolysis (RIP) of FGFR3. The ectodomain is proteolytically cleaved (S1) in response to ligand-induced receptor activation, but unlike most RIP target proteins, it requires endocytosis and does not involve a metalloproteinase. S1 cleavage generates a C-terminal domain fragment that initially remains anchored in the membrane, is phosphorylated, and is spatially distinct from the intact receptor. Ectodomain cleavage is followed by intramembrane cleavage (S2) to generate a soluble intracellular domain that is released into the cytosol and can translocate to the nucleus. We identify the S1 cleavage site and show that γ-secretase mediates the S2 cleavage event. In this way we demonstrate a mechanism for the nuclear localization of FGFR3 in response to ligand activation, which may occur in both development and disease.

scholarly journals In vitro and in vivo characterization of Recifercept, a soluble fibroblast growth factor receptor 3, as treatment for achondroplasia

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244368
Author(s):  
Diogo Gonçalves ◽  
Guylène Rignol ◽  
Pierre Dellugat ◽  
Guido Hartmann ◽  
Stephanie Sarrazy Garcia ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Bone Growth ◽  
Fibroblast Growth Factor Receptor ◽  
Genetic Disorder ◽  
Growth Factor Receptor ◽  
Model Systems ◽  
Long Bone ◽  
Fibroblast Growth

Achondroplasia is a rare genetic disorder caused by mutations in the Fibroblast Growth Factor receptor 3 (FGFR3). These mutations lead to aberrant increase of inhibitory signaling in proliferating chondrocytes at the growth plate. Recifercept is a potential treatment for this disease using a decoy approach to sequester FGFR3 ligands subsequently normalizing activation of the mutated FGFR3 receptor. Recifercept binds to FGF isoforms in vitro and in cellular model systems and reduces FGFR3 signaling. In addition, in a transgenic mouse model of achondroplasia, Recifercept restores reduced body weight and long bone growth in these mice. These data suggest that Recifercept treatment could lead to clinical benefits in children treated with this molecule.

scholarly journals Fibroblast Growth Factor Receptor Signaling in Skin Cancers

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 540 ◽  
Author(s):  
Malgorzata Czyz
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Signaling Pathway ◽  
Fibroblast Growth Factor Receptor ◽  
Uv Light ◽  
Growth Factor Receptor ◽  
Melanoma Cells ◽  
Mitogen Activated Protein Kinase ◽  
Fibroblast Growth ◽  
Fgfr Signaling

Fibroblast growth factor (FGF)/Fibroblast growth factor receptor (FGFR) signaling regulates various cellular processes during the embryonic development and in the adult organism. In the skin, fibroblasts and keratinocytes control proliferation and survival of melanocytes in a paracrine manner via several signaling molecules, including FGFs. FGF/FGFR signaling contributes to the skin surface expansion in childhood or during wound healing, and skin protection from UV light damage. Aberrant FGF/FGFR signaling has been implicated in many disorders, including cancer. In melanoma cells, the FGFR expression is low, probably because of the strong endogenous mutation-driven constitutive activation of the downstream mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) signaling pathway. FGFR1 is exceptional as it is expressed in the majority of melanomas at a high level. Melanoma cells that acquired the capacity to synthesize FGFs can influence the neighboring cells in the tumor niche, such as endothelial cells, fibroblasts, or other melanoma cells. In this way, FGF/FGFR signaling contributes to intratumoral angiogenesis, melanoma cell survival, and development of resistance to therapeutics. Therefore, inhibitors of aberrant FGF/FGFR signaling are considered as drugs in combination treatment. The ongoing LOGIC-2 phase II clinical trial aims to find out whether targeting the FGF/FGFR signaling pathway with BGJ398 may be a good therapeutic strategy in melanoma patients who develop resistance to v-Raf murine sarcoma viral oncogene homolog B (BRAF)/MEK inhibitors.

scholarly journals Fibroblast Growth Factor Receptor 3 Is a Negative Regulator of Bone Growth

Cell ◽  
1996 ◽  
Vol 84 (6) ◽  
pp. 911-921 ◽  
Author(s):  
Chuxia Deng ◽  
Anthony Wynshaw-Boris ◽  
Fen Zhou ◽  
Ann Kuo ◽  
Philip Leder
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Bone Growth ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Negative Regulator ◽  
Fibroblast Growth
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