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

Precise spatiotemporal regulation of parathyroid hormone (PTH) and PTH-related peptide (PTHrP) signaling through the PTH1R is fundamental to skeletal development and metabolic bone remodeling, yet the intracellular mechanisms that fine-tune this signaling remain a central unanswered question. 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. Importantly, Nf2 ablation confers profound resistance to age-related and ovariectomy-induced osteoporosis. These results establish Nf2 as a chondrocyte‐intrinsic gatekeeper of PTH1R signaling and uncover a novel therapeutic paradigm for bone diseases by targeting Nf2‐mediated β-arrestin2 recruitment.