Nf2 orchestrates β-arrestin2-biased PTH1R signaling to safeguard skeletal integrity

Here, we identify neurofibromin 2 (Nf2) as an essential regulator of PTH1R trafficking and signaling. Conditional knockout of Nf2 in chondrocytes results in short-limbed dwarfism, disrupted growth plate organization, and suppressed chondrocyte proliferation and hypertrophy, and a paradoxical bone phenotype marked by trabecular hyperproliferation and cortical thinning.

Mechanistically, Nf2 binds to the PTH1R C-terminal domain (464–591 aa) to promote selective receptor internalization via β-arrestin2, without altering Gαs‐mediated cAMP production or initial receptor phosphorylation by GRKs. Loss of Nf2 decouples PTH1R from β-arrestin2‐mediated endocytosis, leading to sustained and amplified signaling through the cAMP‐CREB‐pSOX9 (S181) and VEGF axis. Consequently, Nf2-deficient mice exhibit exaggerated anabolic responses to the PTH1R agonist abaloparatide and are rescued by the inverse agonist cinacalcet.