Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass Academic Article uri icon

Overview

MeSH Major

  • Feedback, Physiological
  • Membrane Proteins
  • NFATC Transcription Factors
  • Osteoclasts
  • Osteogenesis

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.

publication date

  • December 22, 2015

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4697402

Digital Object Identifier (DOI)

  • 10.1073/pnas.1511285112

PubMed ID

  • 26644563

Additional Document Info

start page

  • 15654

end page

  • 9

volume

  • 112

number

  • 51