FGF18 Represses Noggin Expression and Is Induced by Calcineurin

Abstract

Fibroblast growth factors (FGFs) and bone morphogenetic proteins strongly regulate chondrogenesis and chondrocyte gene expression. The interactions of the signaling pathways initiated by these factors are central to the control of chondrocyte differentiation. Here we show that calcium-dependent signals induce expression of FGF18, an essential regulator of bone and cartilage differentiation. The induction of FGF18 expression required the calcium-dependent phosphatase, calcineurin. The activated forms of calcineurin or the calcineurin-dependent transcription factor, NFAT4 (nuclear factor of activated T-cell 4), induced FGF18 expression. FGF18 or a constitutive active FGF receptor suppressed noggin gene induction and thereby increased chondrocyte gene expression and chondrogenesis by facilitating bone morphogenetic protein-dependent signals. These findings reinforce the interdependence of bone morphogenetic protein and FGF signaling and provide a rational explanation for abnormal bone development occurring in humans or mice with constitutively active FGF receptors. Fibroblast growth factors (FGFs) and bone morphogenetic proteins strongly regulate chondrogenesis and chondrocyte gene expression. The interactions of the signaling pathways initiated by these factors are central to the control of chondrocyte differentiation. Here we show that calcium-dependent signals induce expression of FGF18, an essential regulator of bone and cartilage differentiation. The induction of FGF18 expression required the calcium-dependent phosphatase, calcineurin. The activated forms of calcineurin or the calcineurin-dependent transcription factor, NFAT4 (nuclear factor of activated T-cell 4), induced FGF18 expression. FGF18 or a constitutive active FGF receptor suppressed noggin gene induction and thereby increased chondrocyte gene expression and chondrogenesis by facilitating bone morphogenetic protein-dependent signals. These findings reinforce the interdependence of bone morphogenetic protein and FGF signaling and provide a rational explanation for abnormal bone development occurring in humans or mice with constitutively active FGF receptors. The fibroblast growth factors (FGFs) 1The abbreviations used are: FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; RCJ, RCJ3.1C5.18; BMP, bone morphogenetic protein; TGF, transforming growth factor; BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethylester). and the fibroblast growth factor receptors (FGFRs) are important regulators of cartilage growth and development (1Wilkie A.O. Patey S.J. Kan S.H. van den Ouweland A.M. Hamel B.C. Am. J. Med. 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Holderman S. Holdren M.S. Lum K.D. Moore E.E. Raymond F. Ren H. Shea P. Sprecher C. Storey H. Thompson D.L. Waggie K. Yao L. Fernandes R.J. Eyre D.R. Hughes S.D. Osteoarthritis Cartilage. 2002; 10: 308-320Abstract Full Text PDF PubMed Scopus (162) Google Scholar, 13Shimoaka T. Ogasawara T. Yonamine A. Chikazu D. Kawano H. Nakamura K. Itoh N. Kawaguchi H. J. Biol. Chem. 2002; 277: 7493-7500Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). Consequently, understanding the pathways that regulate FGF18 gene expression should yield direct insight into principal controllers of chondrocyte and osteoblast differentiation. Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily that were first described based on their capacity to induce heterotopic bone (14Urist M.R. Science. 1965; 150: 893-899Crossref PubMed Scopus (4582) Google Scholar). 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Harland R.M. Cell. 1996; 86: 599-606Abstract Full Text Full Text PDF PubMed Scopus (1352) Google Scholar, 25Groppe J. Greenwald J. Wiater E. Rodriguez-Leon J. Economides A.N. Kwiatkowski W. Affolter M. Vale W.W. Belmonte J.C. Choe S. Nature. 2002; 420: 636-642Crossref PubMed Scopus (438) Google Scholar). Noggin expression is rapidly induced following the activation of BMP receptors and therefore acts as an effective feedback antagonist (26Gazzerro E. Gangji V. Canalis E. J. Clin. Investig. 1998; 102: 2106-2114Crossref PubMed Scopus (283) Google Scholar, 27Ito H. Akiyama H. Shigeno C. Nakamura T. Biochem. Biophys. Res. Commun. 1999; 260: 240-244Crossref PubMed Scopus (28) Google Scholar). Noggin is expressed in all developing cartilage and clearly has a vital role as an antagonist of BMP signaling in the regulation of skeletal development. This is evidenced by noggin null mice, which have expanded cartilage elements and joint fusions (28Brunet L.J. McMahon J.A. McMahon A.P. Harland R.M. Science. 1998; 280: 1455-1457Crossref PubMed Scopus (695) Google Scholar). Furthermore, mutations of the human noggin gene cause syndromes with varied joints fusions (29Gong Y. Krakow D. Marcelino J. Wilkin D. Chitayat D. Babul-Hirji R. Hudgins L. Cremers C.W. Cremers F.P. Brunner H.G. Reinker K. Rimoin D.L. Cohn D.H. Goodman F.R. Reardon W. Patton M. Francomano C.A. Warman M.L. Nat. Genet. 1999; 21: 302-304Crossref PubMed Scopus (284) Google Scholar). Therefore, antagonism of BMP signaling by noggin is essential for joint development and determining the size of bone rudiments. Although noggin is induced by BMP signaling, the molecular pathways regulating noggin gene expression are largely uncharacterized. Cytokines or growth factors like FGFs or BMPs and their inhibitors clearly have dramatic effects on chondrocyte gene expression and the development of cartilage. However, relatively little is understood of how these genes are induced or inhibited. Consequently, characterizing the pathways that stimulate growth factor expression will yield insight into the control of chondrogenesis. Many cytokines are induced following receptor-dependent calcium signaling. For example, we have shown that elevations of intracellular calcium induce BMP2 gene expression (30Tomita M. Reinhold M.I. Molkentin J.D. Naski M.C. J. Biol. Chem. 2002; 277: 42214-42218Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). This in turn promotes chondrocyte gene expression and chondrogenesis. To further understand the effects of calcium signaling on growth factor gene expression and chondrogenesis, we investigated the regulation of FGF18 expression. We show that signaling FGF18 as the calcineurin factor of activated T-cell FGF18 noggin gene expression and thereby BMP signaling and chondrogenesis. these the effects of FGFs on chondrocytes and their FGF signaling chondrocyte endochondral M.C. Colvin J.S. J.D. Ornitz D.M. 1998; PubMed Google Scholar, L. R. X. C. A. J. Clin. Investig. 1999; PubMed Scopus Google Scholar, L. T. M. Genet. 1999; PubMed Scopus Google Scholar). However, an of cartilage FGFs stimulate chondrogenesis by noggin FGF and BMP signaling were and in with and bud were in and the bud as described C. J. 1996; PubMed Scopus Google Scholar). cell were limb following with and for with inhibited with an of and the a cell were with growth and as the were with growth noggin a of of chondrocyte in a acid by with and and growth factors were as FGF18 and as described M.C. Xu J. Ornitz D.M. Nat. Genet. 1996; PubMed Scopus Google Scholar), and a A. were cultured on in a The were with FGF18 or BMP2 for or in with The were with 10 in and with and a of used in the a and were a and to the were to the of in for transcription with to the in the to the of were of of and and of were for and for 10 by of and were for with to and to were that the of the a were and for used were as and noggin and and FGF18 and of intracellular were with in 10 and for and with the The were with in for 8 were as described J. De L.J. P. Molkentin J.D. Cell. Biol. 2000; PubMed Scopus Google Scholar). and M. K. T. H. S. M. Kato M. H. K. Biol. Cell. 1999; 10: PubMed Scopus (372) Google were by M. were by a of of 10 that that of the were as by or of the to the of to a were and to were with by Y. of or were with a to the of gene expression were by a For the of to a or and and were as described M.C. Xu J. Ornitz D.M. Nat. Genet. 1996; PubMed Scopus Google Scholar). were with and and and were with to protein were by and to were with the and by with the were to tissue and were as described M.C. Colvin J.S. J.D. Ornitz D.M. 1998; PubMed Google Scholar). The noggin for a R. Harland of were an The null hypothesis for of by of of the limb of chondrogenesis when a cell in M. Dev. Biol. PubMed Scopus Google Scholar). To understand calcium-dependent signaling in this we limb bud with the calcium We that chondrogenesis in these as evidenced by a dramatic in the number of the differentiation of by as shown by increased expression of the These that calcium-dependent signals stimulate chondrocyte and in (30Tomita M. Reinhold M.I. Molkentin J.D. Naski M.C. J. Biol. Chem. 2002; 277: 42214-42218Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar), we show that the calcium-dependent calcineurin. We when calcineurin BMP2 gene expression and that differentiation in these a (30Tomita M. Reinhold M.I. Molkentin J.D. Naski M.C. J. Biol. Chem. 2002; 277: 42214-42218Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). FGF18 To further the effects of calcium-dependent signals on chondrocyte differentiation and gene we calcium signaling FGF18 gene expression. FGF18 is an essential regulator of chondrocyte differentiation endochondral bone growth and thereby a target for the effects of calcium signaling on chondrocyte differentiation. we that FGF18 expression is induced to by the calcium To the signaling pathways required for the induction of FGF18 gene we calcineurin is is a calcium-dependent that is inhibited by A. the induction of FGF18 by the expression of an activated of calcineurin the to induce FGF18 expression in induced FGF18 to a control the transcription factor and calcineurin induced FGF18 expression. of an activated of NFAT4 in induced FGF18 to a control We that the induction of FGF18 gene expression by of intracellular calcium the calcium-dependent phosphatase, calcineurin. To the activation of FGF18 expression by FGF signaling, we FGF receptor activation by with the activation of FGF18 that tyrosine of the FGF the induction of FGF receptor FGF and Noggin calcium-dependent signals induce chondrocyte differentiation and FGF18 we the induction of FGF18 and FGF receptor signaling contribute to chondrogenesis. FGF18 is a for FGF receptor (12Ellsworth J.L. Berry J. Bukowski T. Claus J. Feldhaus A. Holderman S. Holdren M.S. Lum K.D. Moore E.E. Raymond F. Ren H. Shea P. Sprecher C. Storey H. Thompson D.L. Waggie K. Yao L. Fernandes R.J. Eyre D.R. Hughes S.D. Osteoarthritis Cartilage. 2002; 10: 308-320Abstract Full Text PDF PubMed Scopus (162) Google Scholar). Therefore, we used a constitutively active as a for FGF18 to for effects on chondrogenesis. a an into limb bud The of 3, and that FGF receptor signaling strongly differentiation as evidenced by a in the size of the cartilage and a in the number of cartilage in to a control with We that FGF receptor signaling chondrogenesis and that induction of FGF18 expression to chondrocyte differentiation. to chondrogenesis in the limb bud differentiation is on BMP signaling. BMP signaling with receptors or BMP cartilage development Y. T. M. N. M. M. T. A. S. T. 1996; PubMed Google Scholar, S. L. Dev. Biol. 2000; PubMed Scopus Google Scholar). constitutive BMP receptors or BMP differentiation D. M.K. C.W. L. Mech. Dev. 1996; PubMed Scopus Google Scholar, H. R. J. L. Genes Dev. PubMed Scopus Google Scholar). The that FGF signaling chondrogenesis that BMP signaling is by This by including the induction of BMP gene expression or of BMP FGF18 induce the expression of BMP2 or growth differentiation factor However, FGF18 the expression of the BMP Noggin expression induced in by with BMP2 in the or of Noggin induced following the of BMP2 However, noggin induction by the of FGF18 in the in the of with an activated FGF receptor a of noggin expression following with BMP2 with a control of limb bud cell with FGF18 noggin gene expression to control Furthermore, noggin to limb bud FGF18 is induced by in a of chondrogenesis we that noggin expression is in mice an activated in cartilage. and of the growth mice or mice by the M.C. Colvin J.S. J.D. Ornitz D.M. 1998; PubMed Google Scholar). The in that noggin are in the cartilage of the These support the that FGF18 BMP signaling by the expression of the BMP in support of this that FGF18 the expression of a in and of limb bud the induction of by FGF18 is following of BMP signaling inhibitors including BMP receptor or and 7 and the induction of by FGF18 is following the of the BMP noggin of noggin in the growth of and show show the of noggin with a The the of the growth of expression by FGF18 and BMP signaling. of FGF18 BMP2 or on expression. expression by following transcription of effects of FGF18 on the expression of in cultured limb bud bud cultured for in the or of FGF18, and expression by following transcription of of or on expression in the or of FGF18 by the were or with FGF18 for expression by noggin the induction of by were or with FGF18 in the or of noggin expression by were to FGF18 We that FGF18 suppressed the induction of noggin by We that FGF18 BMP signaling this and thereby differentiation. However, is that FGF signaling noggin induction by directly BMP signaling. this we FGF signaling to than differentiation. To FGF signaling BMP signaling, the of FGF18 on BMP receptors directly the receptor-dependent and thereby of and gene expression F. A. J.C. J. J. Harland R.M. J. Nature. 1996; PubMed Scopus Google Scholar). To FGF signaling we the of FGF18 on the and of were by BMP2 in the or of FGF18 and for and by with an that following a with of in all of the in or of with FGF18 and BMP2 and of were and and These support the that signaling pathways activated by FGF18 directly or that FGF signaling BMP signaling or gene we the of FGF signaling on of BMP signaling. shown in 6, and FGF18 than the expression of in limb bud or The expression of a direct target of P. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar), partially inhibited in with FGF18 and BMP2 However, in the expression of following BMP2 of with or constitutive active FGF receptor Therefore, these support the that FGF signaling BMP of expression. of FGF18 BMP2 or on expression. expression by following transcription of of expression in by the were to a FGF18 and These that elevations of intracellular calcium activate (30Tomita M. Reinhold M.I. Molkentin J.D. Naski M.C. J. Biol. Chem. 2002; 277: 42214-42218Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar), we show that signaling BMP2 gene expression. FGF18 and BMP2 cartilage and chondrocyte gene expression. This that ligands that activate this will of chondrogenesis. chondrogenesis and chondrocyte gene expression and is therefore an for a that FGF18 and BMP2 gene expression. the of with induced the expression of FGF18 and BMP2 Furthermore, the calcineurin suppressed the induction of FGF18 by To FGF18 expression the activation of calcium signaling we with the calcium and with intracellular calcium to the activation of FGF18 expression by we that of with inhibited the induction of FGF18 by These that activate a that FGF18 expression. The of with a in noggin gene expression This with a in noggin expression when are with BMP2 This noggin the of noggin expression is FGF18 is (30Tomita M. Reinhold M.I. Molkentin J.D. Naski M.C. J. Biol. Chem. 2002; 277: 42214-42218Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar), we show that BMP2 gene expression and chondrogenesis are induced following activation of calcineurin and the calcineurin Here we that calcineurin the expression of activation of FGF receptor signaling suppressed noggin gene expression and thereby BMP signaling. These are in this stimulate the elevations of intracellular calcineurin is activated and FGF18 and BMP2 expression. FGF18 and BMP2 to stimulate chondrogenesis. Because the induction of FGF18 and BMP2 these the of calcineurin to chondrogenesis and chondrocyte gene expression. The that calcineurin will vital regulators of chondrogenesis. the calcineurin and transcription factor, chondrogenesis and FGF18 and of calcineurin contribute to the regulation of chondrogenesis. Because FGF18 and BMP2 to induce chondrogenesis, ligands that induce the expression of FGF18 and BMP2 should of chondrogenesis. induced FGF18 and and as is a of chondrogenesis in limb bud chondrogenesis and when in developing J. Rodriguez-Leon J. J.A. Y. D. R. J.M. Dev. Biol. 2003; PubMed Scopus Google Scholar, L. Res. PubMed Scopus Google Scholar). the induction of FGF18 by a for calcineurin. Because the activation of calcineurin an with this that calcium in we that of intracellular calcium with strongly inhibited the induction of FGF18 by These support a the elevations of intracellular with this show that in intracellular calcium are in cell with these calcium were to activate calcineurin J.L. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). show A. Y. N. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. L. M. B. E. S. T. Y. L. R. X. Am. 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Biol. 2003; Full Text Full Text PDF PubMed Scopus Google control of FGF with BMP signaling to control the and of the the interdependence of signaling and this by that regulation of noggin expression by FGF signaling in as well as more We that FGF signaling in chondrocytes or noggin expression and that this to cartilage joint FGF signaling as in mice or humans with constitutively active FGF receptors cause of noggin expression and abnormal or Noggin is expressed in and the of or developing joints R. Y. D. Economides A.N. J.M. Dev. Biol. 1998; PubMed Scopus Google Scholar). Therefore, antagonism of BMP signaling by noggin regulate the of joints and the of developing bone with this mice (28Brunet L.J. McMahon J.A. McMahon A.P. Harland R.M. Science. 1998; 280: 1455-1457Crossref PubMed Scopus (695) Google show of joint and cartilage Therefore, the control of noggin expression by FGF signaling is to the size and of bone rudiments. 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