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  • 1
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    FGF signalling regulates bone growth through autophagy (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-11-26
    Description: Skeletal growth relies on both biosynthetic and catabolic processes. While the role of the former is clearly established, how the latter contributes to growth-promoting pathways is less understood. Macroautophagy, hereafter referred to as autophagy, is a catabolic process that plays a fundamental part in tissue homeostasis. We investigated the role of autophagy during bone growth, which is mediated by chondrocyte rate of proliferation, hypertrophic differentiation and extracellular matrix (ECM) deposition in growth plates. Here we show that autophagy is induced in growth-plate chondrocytes during post-natal development and regulates the secretion of type II collagen (Col2), the major component of cartilage ECM. Mice lacking the autophagy related gene 7 (Atg7) in chondrocytes experience endoplasmic reticulum storage of type II procollagen (PC2) and defective formation of the Col2 fibrillary network in the ECM. Surprisingly, post-natal induction of chondrocyte autophagy is mediated by the growth factor FGF18 through FGFR4 and JNK-dependent activation of the autophagy initiation complex VPS34-beclin-1. Autophagy is completely suppressed in growth plates from Fgf18(-/-) embryos, while Fgf18(+/-) heterozygous and Fgfr4(-/-) mice fail to induce autophagy during post-natal development and show decreased Col2 levels in the growth plate. Strikingly, the Fgf18(+/-) and Fgfr4(-/-) phenotypes can be rescued in vivo by pharmacological activation of autophagy, pointing to autophagy as a novel effector of FGF signalling in bone. These data demonstrate that autophagy is a developmentally regulated process necessary for bone growth, and identify FGF signalling as a crucial regulator of autophagy in chondrocytes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cinque, Laura -- Forrester, Alison -- Bartolomeo, Rosa -- Svelto, Maria -- Venditti, Rossella -- Montefusco, Sandro -- Polishchuk, Elena -- Nusco, Edoardo -- Rossi, Antonio -- Medina, Diego L -- Polishchuk, Roman -- De Matteis, Maria Antonietta -- Settembre, Carmine -- England -- Nature. 2015 Dec 10;528(7581):272-5. doi: 10.1038/nature16063. Epub 2015 Nov 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei, 34, 80078 Pozzuoli (NA), Italy. ; Dulbecco Telethon Institute, Via Campi Flegrei, 34, 80078 Pozzuoli (NA), Italy. ; Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Via Pansini 5, 80131 Naples, Italy. ; Department of Molecular Medicine, Biochemistry Unit, University of Pavia, 27100 Pavia, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26595272" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy/genetics/*physiology ; Bone Development/genetics/*physiology ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; Chondrocytes/cytology/metabolism ; Collagen Type II/secretion ; Embryo, Mammalian ; Extracellular Matrix/genetics ; Fibroblast Growth Factors/*genetics/metabolism ; Growth Plate/cytology/metabolism ; MAP Kinase Signaling System ; Mice ; Microtubule-Associated Proteins/genetics/metabolism ; Receptor, Fibroblast Growth Factor, Type 4/genetics/metabolism ; *Signal Transduction
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Lysosomal Enhancement by Genistein [Metabolism] (2014)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
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    Publication Date: 2014-06-14
    Description: Genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) has been previously proposed as a potential drug for use in substrate reduction therapy for mucopolysaccharidoses, a group of inherited metabolic diseases caused by mutations leading to inefficient degradation of glycosaminoglycans (GAGs) in lysosomes. It was demonstrated that this isoflavone can cross the blood-brain barrier, making it an especially desirable potential drug for the treatment of neurological symptoms present in most lysosomal storage diseases. So far, no comprehensive genomic analyses have been performed to elucidate the molecular mechanisms underlying the effect elicited by genistein. Therefore, the aim of this work was to identify the genistein-modulated gene network regulating GAG biosynthesis and degradation, taking into consideration the entire lysosomal metabolism. Our analyses identified over 60 genes with known roles in lysosomal biogenesis and/or function whose expression was enhanced by genistein. Moreover, 19 genes whose products are involved in both GAG synthesis and degradation pathways were found to be remarkably differentially regulated by genistein treatment. We found a regulatory network linking genistein-mediated control of transcription factor EB (TFEB) gene expression, TFEB nuclear translocation, and activation of TFEB-dependent lysosome biogenesis to lysosomal metabolism. Our data indicate that the molecular mechanism of genistein action involves not only impairment of GAG synthesis but more importantly lysosomal enhancement via TFEB. These findings contribute to explaining the beneficial effects of genistein in lysosomal storage diseases as well as envisage new therapeutic approaches to treat these devastating diseases.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
    Published by The American Society for Biochemistry and Molecular Biology (ASBMB)
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