Abstract

Significance This study identifies neurofibromin 2 (Nf2) as a critical regulator of parathyroid hormone (PTH) and PTH-related peptide (PTHrP) signaling. Nf2 specifically promotes β-arrestin2-coupled receptor internalization, decoupling this endocytic pathway from canonical G-protein signaling. This mechanism critically determines skeletal homeostasis by influencing bone anabolism and catabolism. Our findings establish Nf2 as a chondrocyte-intrinsic modulator of PTH1R trafficking, providing a mechanistic basis for understanding how bone balances its structure and integrity, where both bone mass and quality are comprised.