Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass

Area of Science:

• Skeletal Biology
• Immunology
• Cell Signaling

Background:

• Phospholipase C gamma-2 (PLCγ2) signaling and calcium (Ca2+) oscillations are crucial for nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) activation, driving osteoclastogenesis.
• Osteoclastogenesis is vital for skeletal remodeling but also implicated in pathological bone loss.

Purpose of the Study:

• To identify the function of transmembrane protein 178 (Tmem178), a PLCγ2 downstream target, in regulating the NFATc1 axis.
• To investigate the role of Tmem178 in skeletal homeostasis and pathological bone loss.

Main Methods:

• Utilized knockout mouse models (Tmem178(-/-) and PLCγ2(-/-)) to assess skeletal phenotypes.
• Investigated Tmem178 localization and function in regulating calcium fluxes at the ER membrane.
• Analyzed human CD14(+) monocytes from patients with systemic juvenile idiopathic arthritis.

Main Results:

• Tmem178(-/-) mice exhibit osteopenia and increased susceptibility to inflammatory bone loss due to enhanced osteoclast formation, contrasting with PLCγ2(-/-) mice.
• Tmem178 localizes to the ER membrane and modulates RANKL-induced Ca2+ fluxes, thereby controlling NFATc1 induction.
• Down-regulation of Tmem178 in human monocytes correlates with excessive osteoclastogenesis, particularly in patients with systemic juvenile idiopathic arthritis.

Conclusions:

• Tmem178 acts as a critical modulator of the NFATc1 axis, essential for maintaining skeletal mass.
• Tmem178 plays a key role in limiting pathological bone loss by controlling osteoclast formation.
• Dysregulation of Tmem178 is linked to excessive osteoclastogenesis and bone loss in inflammatory conditions.