title: The collection of NFATc1-dependent transcripts in the osteoclast includes numerous genes non-essential to physiologic bone resorption.
abstract: Osteoclasts are specialized secretory cells of the myeloid lineage important for normal skeletal homeostasis as well as pathologic conditions of bone including osteoporosis, inflammatory arthritis and cancer metastasis. Differentiation of these multinucleated giant cells from precursors is controlled by the cytokine RANKL, which through its receptor RANK initiates a signaling cascade culminating in the activation of transcriptional regulators which induce the expression of the bone degradation machinery. The transcription factor nuclear factor of activated T-cells c1 (NFATc1) is the master regulator of this process and in its absence osteoclast differentiation is aborted both in vitro and in vivo. Differential mRNA expression analysis by microarray is used to identify genes of potential physiologic relevance across nearly all biologic systems. We compared the gene expression profile of murine wild-type and NFATc1-deficient osteoclast precursors stimulated with RANKL and identified that the majority of the known genes important for osteoclastic bone resorption require NFATc1 for induction. Here, five novel RANKL-induced, NFATc1-dependent transcripts in the osteoclast are described: Nhedc2, Rhoc, Serpind1, Adcy3 and Rab38. Despite reasonable hypotheses for the importance of these molecules in the bone resorption pathway and their dramatic induction during differentiation, the analysis of mice with mutations in these genes failed to reveal a function in osteoclast biology. Compared to littermate controls, none of these mutants demonstrated a skeletal phenotype in vivo or alterations in osteoclast differentiation or function in vitro. These data highlight the need for rigorous validation studies to complement expression profiling results before functional importance can be assigned to highly regulated genes in any biologic process.
authors.affiliation: Department of Medicine, Division of Rheumatology, Allergy and Immunology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Julia F
authors.initials: JF
authors.lastname: Charles
authors.forename: Fabienne
authors.initials: F
authors.lastname: Coury
authors.forename: Rosalyn
authors.initials: R
authors.lastname: Sulyanto
authors.forename: Despina
authors.initials: D
authors.lastname: Sitara
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Nicholas
authors.initials: N
authors.lastname: Brady
authors.forename: Kelly
authors.initials: K
authors.lastname: Tsang
authors.forename: Kirsten
authors.initials: K
authors.lastname: Sigrist
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Tollefsen
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.forename: Daniel
authors.initials: D
authors.lastname: Storm
authors.forename: Antonios O
authors.initials: AO
authors.lastname: Aliprantis
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001862:Bone Resorption / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053245:RANK Ligand / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D000075024:rhoC GTP-Binding Protein
chemical_list: D050778:NFATC Transcription Factors; D053245:RANK Ligand; D017923:Sodium-Hydrogen Exchangers; C498786:Rab38 protein, mouse; C512911:Rhoc protein, mouse; D020691:rab GTP-Binding Proteins; D018631:ras Proteins; D000075024:rhoC GTP-Binding Protein; D000262:Adenylyl Cyclases; C421784:adenylate cyclase 3