{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:29:32Z","timestamp":1787005772993,"version":"build-2736575974"},"reference-count":69,"publisher":"National Academy of Sciences","issue":"24","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No.82571024"],"award-info":[{"award-number":["No.82571024"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,6,16]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic toggle=\"yes\">Nf2<\/jats:italic>\n                    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\u2013591 aa) to promote selective receptor internalization via \u03b2-arrestin2 without altering G protein\u2013coupled receptor kinase-mediated PTH1R phosphorylation. Loss of\n                    <jats:italic toggle=\"yes\">Nf2<\/jats:italic>\n                    decouples PTH1R from \u03b2-arrestin2\u2010mediated endocytosis, leading to sustained and amplified signaling through the cAMP\u2010CREB\u2010pSOX9 (S181) and VEGF axis. Consequently,\n                    <jats:italic toggle=\"yes\">Nf2<\/jats:italic>\n                    -deficient mice exhibited bone changes similar to those induced by the PTH1R agonist abaloparatide. These findings establish Nf2 as a chondrocyte\u2010intrinsic gatekeeper of PTH1R signaling and uncover a cellular mechanism for bone homeostasis by targeting Nf2\u2010mediated \u03b2-arrestin2 recruitment.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2524671123","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T17:38:23Z","timestamp":1781113103000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Nf2 orchestrates \u03b2-arrestin2-biased PTH1R signaling to couple bone mass with skeletal integrity"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0562-1178","authenticated-orcid":false,"given":"Junguang","family":"Liao","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03893we55","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New 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