title: Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass.
abstract: Phospholipase C gamma-2 (PLCγ2)-dependent calcium (Ca(2+)) oscillations are indispensable for nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) activation and downstream gene transcription driving osteoclastogenesis during skeletal remodeling and pathological bone loss. Here we describe, to our knowledge, the first known function of transmembrane protein 178 (Tmem178), a PLCγ2 downstream target gene, as a critical modulator of the NFATc1 axis. In surprising contrast to the osteopetrotic phenotype of PLCγ2(-/-) mice, Tmem178(-/-) mice are osteopenic in basal conditions and are more susceptible to inflammatory bone loss, owing to enhanced osteoclast formation. Mechanistically, Tmem178 localizes to the ER membrane and regulates RANKL-induced Ca(2+) fluxes, thus controlling NFATc1 induction. Importantly, down-regulation of Tmem178 is observed in human CD14(+) monocytes exposed to plasma from systemic juvenile idiopathic arthritis patients. Similar to the mouse model, reduced Tmem178 expression in human cells correlates with excessive osteoclastogenesis. In sum, these findings identify an essential role for Tmem178 to maintain skeletal mass and limit pathological bone loss.
authors.affiliation: Department of Orthopaedic Surgery, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO 63110; Graduate Program in Immunology, Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO 63110;
authors.forename: Corinne E
authors.initials: CE
authors.lastname: Decker
authors.affiliation: Department of Orthopaedic Surgery, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Zhengfeng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Division of Bone and Mineral Diseases, Department of Medicine, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Ryan
authors.initials: R
authors.lastname: Rimer
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021;
authors.forename: Kyung-Hyun
authors.initials: KH
authors.lastname: Park-Min
authors.affiliation: Department of Pediatrics, Program in Immunology, Stanford University, Stanford, CA 94305-5164.
authors.forename: Claudia
authors.initials: C
authors.lastname: Macaubas
authors.affiliation: Department of Pediatrics, Program in Immunology, Stanford University, Stanford, CA 94305-5164.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Mellins
authors.affiliation: Division of Bone and Mineral Diseases, Department of Medicine, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Deborah V
authors.initials: DV
authors.lastname: Novack
authors.affiliation: Department of Orthopaedic Surgery, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO 63110; faccior@wustl.edu.
authors.forename: Roberta
authors.initials: R
authors.lastname: Faccio
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D025461:Feedback, Physiological; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000502:physiology*; D010010:Osteoclasts / Q000502:physiology*; D010012:Osteogenesis; D051966:Phospholipase C gamma / Q000502:physiology
chemical_list: D008565:Membrane Proteins; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C494005:Nfatc1 protein, mouse; C000608178:transmembrane protein 178, human; C000608179:transmembrane protein 178, mouse; D051966:Phospholipase C gamma; D002118:Calcium
keywords: NFATc1; Tmem178; calcium; osteoclasts; sJIA