title: A RANKL-PKCβ-TFEB signaling cascade is necessary for lysosomal biogenesis in osteoclasts.
abstract: Bone resorption by osteoclasts requires a large number of lysosomes that release proteases in the resorption lacuna. Whether lysosomal biogenesis is a consequence of the action of transcriptional regulators of osteoclast differentiation or is under the control of a different and specific transcriptional pathway remains unknown. We show here, through cell-based assays and cell-specific gene deletion experiments in mice, that the osteoclast differentiation factor RANKL promotes lysosomal biogenesis once osteoclasts are differentiated through the selective activation of TFEB, a member of the MITF/TFE family of transcription factors. This occurs following PKCβ phosphorylation of TFEB on three serine residues located in its last 15 amino acids. This post-translational modification stabilizes and increases the activity of this transcription factor. Supporting these biochemical observations, mice lacking in osteoclasts--either TFEB or PKCβ--show decreased lysosomal gene expression and increased bone mass. Altogether, these results uncover a RANKL-dependent signaling pathway taking place in differentiated osteoclasts and culminating in the activation of TFEB to enhance lysosomal biogenesis-a necessary step for proper bone resorption.
authors.affiliation: Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Ferron
authors.forename: Carmine
authors.initials: C
authors.lastname: Settembre
authors.forename: Junko
authors.initials: J
authors.lastname: Shimazu
authors.forename: Julie
authors.initials: J
authors.lastname: Lacombe
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D011499:Protein Processing, Post-Translational; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D053245:RANK Ligand; C484068:Tcfeb protein, mouse; C505689:Tnfsf11 protein, mouse; D011493:Protein Kinase C; D064546:Protein Kinase C beta