Nf2 orchestrates β-arrestin2-biased PTH1R signaling to couple bone mass with skeletal integrity
Abstract
Precise spatiotemporal regulation of parathyroid hormone (PTH) and PTH-related peptide signaling through the parathyroid hormone receptor 1 (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 G protein–coupled receptor kinase-mediated PTH1R phosphorylation. 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 exhibited bone changes similar to those induced by the PTH1R agonist abaloparatide. These findings establish Nf2 as a chondrocyte‐intrinsic gatekeeper of PTH1R signaling and uncover a cellular mechanism for bone homeostasis by targeting Nf2‐mediated β-arrestin2 recruitment.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (10)
Junguang Liao
Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University
Yiliang He
Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University
Chenyang Zhang
Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University
Qitao Qian
Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University
Yuping Huang
Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University
Qi Zhang
Panpan Shen
Chenhe Zhou
Department of Orthopedics, Second Affiliated Hospital, Zhejiang University School of Medicine
Mengrui Wu
Department of Cell and Developmental Biology, College of Life Sciences, Zhejiang University
Guiqian Chen
Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University