FGF signalling regulates bone growth through autophagy

Cinque, Laura; Forrester, Alison; Bartolomeo, Rosa; Svelto, María; Venditti, Rossella; Montefusco, Sandro; Polishchuk, Elena; Nusco, Edoardo; Rossi, Antonio; Medina, Diego L.; Polishchuk, Roman; Matteis, Maria Antonietta De; Settembre, Carmine

doi:10.1038/nature16063

Cited by 173 publications

(180 citation statements)

References 30 publications

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“…When administered to mice, Tat-Beclin 1 is able to activate autophagy in growth plate chondrocytes (20). We observed that Tat-Beclin 1 administration to WT mice did not affect bone length, growth plate morphology, or chondrocyte function (Supplemental Figure 6, C-E), consistent with previous results (20).…”

Section: Gfp-lc3supporting

confidence: 81%

“…Interestingly, the analysis of craniofacial and dental abnormalities in a LSD mouse model, namely mucolipidosis II (MLII), showed a loss of collagen fibril organization (41), which strikingly resembles the one observed in the cartilage of mice lacking ATG7 in chondrocytes (20).…”

Section: Gfp-lc3mentioning

confidence: 99%

“…We recently demonstrated that autophagy in chondrocytes, the main cells deputed to bone growth, removes defective and excessive collagen molecules from the ER, thereby clearing folding and assembly machineries in the secretory pathway (20). Mice that lack an active autophagy pathway in chondrocytes (in which the Atg7 gene has been deleted) display defective collagen secretion, characterized by intracellular accumulation of type II procollagen (PC2) and lower COL II levels in the ECM and resulting in impaired postnatal bone growth (20).…”

Section: Introductionmentioning

confidence: 99%

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mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy

Bartolomeo

Cinque

Leonibus

et al. 2017

Journal of Clinical Investigation

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The mammalian target of rapamycin complex 1 (mTORC1) kinase promotes cell growth by activating biosynthetic pathways and suppressing catabolic pathways, particularly that of macroautophagy. A prerequisite for mTORC1 activation is its translocation to the lysosomal surface. Deregulation of mTORC1 has been associated with the pathogenesis of several diseases, but its role in skeletal disorders is largely unknown. Here, we show that enhanced mTORC1 signaling arrests bone growth in lysosomal storage disorders (LSDs). We found that lysosomal dysfunction induces a constitutive lysosomal association and consequent activation of mTORC1 in chondrocytes, the cells devoted to bone elongation. mTORC1 hyperphosphorylates the protein UV radiation resistance-associated gene (UVRAG), reducing the activity of the associated Beclin 1-Vps34 complex and thereby inhibiting phosphoinositide production. Limiting phosphoinositide production leads to a blockage of the autophagy flux in LSD chondrocytes. As a consequence, LSD chondrocytes fail to properly secrete collagens, the main components of the cartilage extracellular matrix. In mouse models of LSD, normalization of mTORC1 signaling or stimulation of the Beclin 1-Vps34-UVRAG complex rescued the autophagy flux, restored collagen levels in cartilage, and ameliorated the bone phenotype. Taken together, these data unveil a role for mTORC1 and autophagy in the pathogenesis of skeletal disorders and suggest potential therapeutic approaches for the treatment of LSDs

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Section: Gfp-lc3supporting

confidence: 81%

Section: Gfp-lc3mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy

Bartolomeo

Cinque

Leonibus

et al. 2017

Journal of Clinical Investigation

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“…In this study, we took advantage of Tat-beclin1 (Tat-Bec), a specific autophagy-inducing peptide (40), which has been used to enhance autophagy both in vitro and in vivo (41,42). We found that treatment with Tat-Bec with optimized protocol caused an increase in autophagy activity, promoted axonal growth of CNS neurons cultured on a nonpermissive substrate, and prevented axonal degeneration following injury.…”

mentioning

confidence: 99%

Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury

Ding

Chu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

156

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Remodeling of cytoskeleton structures, such as microtubule assembly, is believed to be crucial for growth cone initiation and regrowth of injured axons. Autophagy plays important roles in maintaining cellular homoeostasis, and its dysfunction causes neuronal degeneration. The role of autophagy in axon regeneration after injury remains speculative. Here we demonstrate a role of autophagy in regulating microtubule dynamics and axon regeneration. We found that autophagy induction promoted neurite outgrowth, attenuated the inhibitory effects of nonpermissive substrate myelin, and decreased the formation of retraction bulbs following axonal injury in cultured cortical neurons. Interestingly, autophagy induction stabilized microtubules by degrading SCG10, a microtubule disassembly protein in neurons. In mice with spinal cord injury, local administration of a specific autophagy-inducing peptide, Tat-beclin1, to lesion sites markedly attenuated axonal retraction of spinal dorsal column axons and cortical spinal tract and promoted regeneration of descending axons following long-term observation. Finally, administration of Tat-beclin1 improved the recovery of motor behaviors of injured mice. These results show a promising effect of an autophagyinducing reagent on injured axons, providing direct evidence supporting a beneficial role of autophagy in axon regeneration.autophagy | microtubule stabilization | axon regeneration I t is generally believed that the inability of adult central nervous system (CNS) neurons to regenerate their axons following injury is due to the presence of abundant inhibitory factors in extrinsic milieu and the lack of intrinsic growth ability (1-5). A number of extrinsic growth-inhibitory factors have been identified, including oligodendrocyte-derived myelin-associated glycoprotein (MAG), Nogo, OMgp, or astrocyte-derived chondroitin sulfate proteoglycans (CSPGs), which act through their respective receptors to suppress axon growth and regeneration (6-11). However, genetic ablation or elimination of these inhibitory receptors does not promote axon regeneration (12, 13) or shows marginal effects (14, 15).Many inhibitory factors act through signaling cascades to modulate cytoskeletal dynamics (16,17). Indeed, it has been observed that CNS axons form numerous retraction bulbs (RBs) with a disorganized array of microtubules (MTs), whereas peripheral nervous system (PNS) axons rapidly form a growth cone with stable, well-organized bundling of MTs following injury (18). In line with this notion, pharmacological stabilization of MTs promotes axon regeneration after spinal cord injury (SCI) (19,20). In addition, analyses of gene-targeted mice have led to identification of several intrinsic inhibitors of axon regeneration in the adult CNS, including phosphatase and tensin homolog (PTEN) and the suppressor of cytokine signaling 3 (SOCS3) (21,22). However, manipulating individual proteins or in combinations allows limited axonal regeneration or sprouting, which is usually associated with temporary improvement ...

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“…In the absence of autophagy, collagen molecules abnormally accumulated within the endoplasmic reticulum (ER) of chondrocytes and the levels of Col2 in the cartilaginous ECM was lower in Atg7 chKO compared to control mice. 2 Collagens are synthesized as precursors (procollagens, PCs) in the ER, and undergo several post-translational modifications, which permit the folding and assembly of native triple helix PC chains that are then secreted into the ECM. PCs are large and complex molecules that can be prone to misfolding during assembly and secretion processes.…”

mentioning

confidence: 99%