Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix homeostasis

Krejčı́, Pavel; Masri, Bernard; Fontaine, Vincent; Mekikian, Pertchoui B.; Weis, MaryAnn; Prats, Hervé; Wilcox, William R.

doi:10.1242/jcs.02618

Cited by 141 publications

(155 citation statements)

References 47 publications

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“…3). Since Raf-1 but not B-Raf is activated by FGF2-treatment in RCS cells (5), it appears that Raf-1 is the principal MEK kinase employed by FGF signaling, and its activation is mediated by Ras (Figs. 2 and 3).…”

Section: Discussionmentioning

confidence: 99%

“…In cartilage, FGFR3 alters chondrocyte proliferation and differentiation by up-regulation of cell cycle inhibitors and stimulation of cartilage matrix degradation (2)(3)(4)(5). The anti-proliferative action of FGF 2 signaling in cartilage contrasts with the usual mitogenic response of cells to FGF stimulus (6), but the molecular basis of this paradox remains unclear.…”

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confidence: 99%

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Bisindolylmaleimide I Suppresses Fibroblast Growth Factor-mediated Activation of Erk MAP Kinase in Chondrocytes by Preventing Shp2 Association with the Frs2 and Gab1 Adaptor Proteins

Krejčı́

Masri

Salazar

et al. 2007

Journal of Biological Chemistry

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Activating mutations in fibroblast growth factor receptor 3 (FGFR3) cause several human dwarfisms characterized by diminished long bone growth (1). In cartilage, FGFR3 alters chondrocyte proliferation and differentiation by up-regulation of cell cycle inhibitors and stimulation of cartilage matrix degradation (2-5). The anti-proliferative action of FGF 2 signaling in cartilage contrasts with the usual mitogenic response of cells to FGF stimulus (6), but the molecular basis of this paradox remains unclear. Recently, Erk MAP kinase was found as a candidate for FGFR3-mediated inhibition of chondrocyte proliferation and differentiation (7-10).Protein kinase C (PKC) comprises a family of serine/threonine kinases that phosphorylate the consensus motif RXX(S/T)XR (11). The PKCs are further divided into three subfamilies based on sequence similarities and modes of activation. The conventional PKCs (PKC␣, -␤I, -␤II, and -␥) are activated by phosphatidylserine, diacylglycerol, and Ca 2ϩ , the novel PKCs (PKC␦, -⑀, -, and -) require only phosphatidylserine and diacylglycerol, and the atypical PKCs (aPKC; PKC and -) respond to phosphatidylserine alone (12). The PKC phosphorylation motif is present in many proteins (13), implicating PKCs as broad specificity protein kinases. PKCs are involved in numerous signaling events including activation of the Erk MAP kinase pathway. This is evident by potent Erk activation in cells treated with phorbol esters, such as phorbol-12-myristate-13-acetate (PMA), which activates both conventional PKCs and novel PKCs through binding of their diacylglycerol site (14). In PMA-treated cells, PKCs target the Erk module at the level of both Raf-1 and MEK, through direct activatory phosphorylation or indirectly (15-21). Apart from PMA-mediated Erk activation, PKCs appear to be crucial for long term Erk activation by growth factors, including FGFs (20,[22][23][24][25], as well as for oncogenic .FGF signaling in chondrocytes leads to long term Ras/Erk activation, which appears to account for the growth inhibitory outcome of FGF treatment (8, 9). To date, little is known about chondrocyte properties of FGF signaling permitting prolonged Erk activity, although slow down-regulation of mutated FGFR3 appears to be involved (30,31).

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Bisindolylmaleimide I Suppresses Fibroblast Growth Factor-mediated Activation of Erk MAP Kinase in Chondrocytes by Preventing Shp2 Association with the Frs2 and Gab1 Adaptor Proteins

Krejčı́

Masri

Salazar

et al. 2007

Journal of Biological Chemistry

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“…Further in vitro study using rat chondrosarcoma chondrocytes from another laboratory revealed that CNP inhibited ERK pathway of FGF signaling at the level of Raf-1 through the activation of cGKII (Fig. 5) [48].…”

Section: Ii-2 the Therapeutic Effect Of Cnp On The Impaired Skeletalmentioning

confidence: 94%

Translational research of C-type natriuretic peptide (CNP) into skeletal dysplasias

Yasoda

Nakao

2010

Endocr J

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Abstract. By using transgenic and knockout mice, we have elucidated that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth. In humans, loss-of-function mutations in the gene coding for guanylyl cyclase-B (GC-B), the specific receptor for CNP, have been proved to be the cause of acromesomelic dysplasia, type Maroteaux, one form of human skeletal dysplasias. Following these results, we have started to translate the stimulatory effect of CNP on endochondral bone growth into the therapy for patients with skeletal dysplasias. We have shown that targeted overexpression of CNP in cartilage or systemic administration of CNP reverses the impaired skeletal growth of mice model of achondroplasia, the most common form of human skeletal dysplasias. Key words: C-type natriuretic peptide (CNP), Guanylyl cyclase-B (GC-B), Skeletal dysplasia, Achondroplasia, Translational researchThe nATriureTic peptide family consists of three structurally related peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) [1]. The biological actions of natriuretic peptides are mediated by activation of two subtypes of membranous guanylyl cyclase (GC), GC-A and GC-B, followed by intracellular accumulation of cyclic GMP (cGMP) [2]. The rank order of potency to induce cGMP production via GC-A is ANP ≥ BNP >> CNP, while that via GC-B is CNP > ANP ≥ BNP [3]. Therefore, ANP and BNP serve as endogenous ligands for GC-A, whereas CNP is specific for GC-B. A third natriuretic peptide receptor with no intracellular guanylyl cyclase domain, dubbed the clearance receptor (C-receptor), is thought to be engaged in the receptor-mediated degradation of natriuretic peptides [2]. The ANP, BNP/GC-A system plays a pivotal role in the regulation of cardiovascular homeostasis, as demonstrated by their augmentation in various pathophysiological states such as heart failure [4][5][6][7][8], myocardial infarction [9, 10], cardiac hypertrophy [11,12], and hypertension [13][14][15]. In fact, ANP and BNP are cardiac hormones secreted primarily by the atrium and ventricle of the heart, respectively [8,15], with strong diuretic, natriuretic, and vasodilatory activities [4, 5, 8]. ANP and BNP are used in the treatment of heart failure [16,17] and serve as sensitive biochemical markers for heart failure and cardiac hypertrophy [6][7][8]. CNP, the third member of natriuretic peptide family, was first purified from porcine brain [18]. While CNP is the primary natriuretic peptide in the human brain [19], it is also produced by vascular endothelial cells [20][21][22] and macrophages [23], and is thought to act as an autocrine/paracrine regulator and as a neuropeptide [19]. Furthermore, analysis of genetically engineered mice of the CNP/GC-B system revealed that CNP and GC-B play a pivotal role in the regulation of endochondral bone growth.i. The growth promoting effect of the cnP/Gc-B system on endochondral bone growth I-1. Skeletal phenotypes of genetically engineered mice of the CNP/GC-B sys...

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“…RCS chondrocytes respond to FGFR3 activation (via exogenous FGF2 addition) with potent growth arrest, loss of the cartilage-like extracellular matrix, and marked alteration of their cellular shape (9,11,12). We have taken advantage of this response and adapted the FGF2/FGFR3-mediated growth arrest for rapid screening of chemical compounds for their activity against FGFR3 signaling (7).…”

Section: Nf449 Inhibits Fgfr3 Signaling In Chondrocytes-mentioning

confidence: 99%

“…We next compared the NF449 effect with that of C-natriuretic peptide, which is a recently discovered inhibitor of FGFR3 signaling (12,13). Fig.…”

Section: Nf449 Inhibits Fgfr3 Signaling In Chondrocytes-mentioning

confidence: 99%

NF449 Is a Novel Inhibitor of Fibroblast Growth Factor Receptor 3 (FGFR3) Signaling Active in Chondrocytes and Multiple Myeloma Cells

Krejčı́

Murakami

Procházková

et al. 2010

Journal of Biological Chemistry

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The FGFR3 receptor tyrosine kinase represents an attractive target for therapy due to its role in several human disorders, including skeletal dysplasias, multiple myeloma, and cervical and bladder carcinomas. By using molecular library screening, we identified a compound named NF449 with inhibitory activity toward FGFR3 signaling. In cultured chondrocytes and murine limb organ culture, NF449 rescued FGFR3-mediated extracellular matrix loss and growth inhibition, which represent two major cellular phenotypes of aberrant FGFR3 signaling in cartilage. Similarly, NF449 antagonized FGFR3 action in the multiple myeloma cell lines OPM2 and KMS11, as evidenced by NF449-mediated reversal of ERK MAPK activation and transcript accumulation of CCL3 and CCL4 chemokines, both of which are induced by FGFR3 activation. In cell-free kinase assays, NF449 inhibited the kinase activity of both wild type and a disease-associated FGFR3 mutant (K650E) in a fashion that appeared non-competitive with ATP. Our data identify NF449 as a novel antagonist of FGFR3 signaling, useful for FGFR3 inhibition alone or in combination with inhibitors that target the ATP binding site.FGFR3 (fibroblast growth factor receptor 3) is a transmembrane tyrosine kinase that serves as a receptor for the members of the fibroblast growth factor (FGF) 2 family and functions in many biological processes, including cell proliferation, differentiation, migration, and survival. To date, activating mutations in FGFR3 have been associated with several human disorders, such as skeletal dysplasias, multiple myeloma, and cervical and bladder carcinomas (1-4).Among the skeletal dysplasias, activating FGFR3 mutations cause achondroplasia, the most common form of human skeletal dysplasia, and thanatophoric dysplasia, the most common form of lethal skeletal dysplasia (1). Long bones of individuals suffering from FGFR3-related skeletal dysplasias show markedly shortened zones of chondrocyte proliferation and differentiation, whereas Fgfr3 knock-out mice and humans without functional FGFR3 demonstrate skeletal overgrowth, together implying the role of FGFR3 as a negative regulator of bone growth (5).Apart from cartilage, ϳ15% of patients suffering from multiple myeloma markedly up-regulate FGFR3 as a consequence of a t(4;14)(p16.3;q32) translocation, with a fraction of patients also harboring activating mutations in FGFR3, identical to those found in the skeletal dysplasias (2, 3). Ectopic expression of FGFR3 enhances multiple myeloma cell proliferation and survival, demonstrating the oncogenic potential of FGFR3 (6).Given its role in human disease, FGFR3 signaling represents an attractive target for therapy. There is no treatment available for achondroplasia at present, thus inciting the development of novel approaches to target FGFR3. The aim of this study was to identify novel inhibitors of FGFR3 signaling in cellular environments relevant to FGFR3-related disorders. We recently established a chondrocyte cell-based reporter assay suitable for identification of inhibitors of ...

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Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix homeostasis

Cited by 141 publications

References 47 publications

Bisindolylmaleimide I Suppresses Fibroblast Growth Factor-mediated Activation of Erk MAP Kinase in Chondrocytes by Preventing Shp2 Association with the Frs2 and Gab1 Adaptor Proteins

Bisindolylmaleimide I Suppresses Fibroblast Growth Factor-mediated Activation of Erk MAP Kinase in Chondrocytes by Preventing Shp2 Association with the Frs2 and Gab1 Adaptor Proteins

Translational research of C-type natriuretic peptide (CNP) into skeletal dysplasias

NF449 Is a Novel Inhibitor of Fibroblast Growth Factor Receptor 3 (FGFR3) Signaling Active in Chondrocytes and Multiple Myeloma Cells

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