{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T10:43:52Z","timestamp":1780569832747,"version":"3.54.1"},"reference-count":49,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T00:00:00Z","timestamp":1679529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"Duke School of Medicine","doi-asserted-by":"publisher","award":["R03 AR059286"],"award-info":[{"award-number":["R03 AR059286"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"Duke School of Medicine","doi-asserted-by":"publisher","award":["F31 HL128029"],"award-info":[{"award-number":["F31 HL128029"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"Duke School of Medicine","doi-asserted-by":"publisher","award":["R01 AR071722"],"award-info":[{"award-number":["R01 AR071722"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"Duke School of Medicine","doi-asserted-by":"publisher","award":["787270"],"award-info":[{"award-number":["787270"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Research Council (ERC)","award":["R03 AR059286"],"award-info":[{"award-number":["R03 AR059286"]}]},{"name":"European Research Council (ERC)","award":["F31 HL128029"],"award-info":[{"award-number":["F31 HL128029"]}]},{"name":"European Research Council (ERC)","award":["R01 AR071722"],"award-info":[{"award-number":["R01 AR071722"]}]},{"name":"European Research Council (ERC)","award":["787270"],"award-info":[{"award-number":["787270"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Paget\u2019s Disease of Bone (PDB) is a metabolic bone disease that is characterized by dysregulated osteoclast function leading to focal abnormalities of bone remodeling. It can lead to pain, fracture, and bone deformity. G protein-coupled receptor kinase 3 (GRK3) is an important negative regulator of G protein-coupled receptor (GPCR) signaling. GRK3 is known to regulate GPCR function in osteoblasts and preosteoblasts, but its regulatory function in osteoclasts is not well defined. Here, we report that Grk3 expression increases during osteoclast differentiation in both human and mouse primary cells and established cell lines. We also show that aged mice deficient in Grk3 develop bone lesions similar to those seen in human PDB and other Paget\u2019s Disease mouse models. We show that a deficiency in Grk3 expression enhances osteoclastogenesis in vitro and proliferation of hematopoietic osteoclast precursors in vivo but does not affect the osteoclast-mediated bone resorption function or cellular senescence pathway. Notably, we also observe decreased Grk3 expression in peripheral blood mononuclear cells of patients with PDB compared with age- and gender-matched healthy controls. Our data suggest that GRK3 has relevance to the regulation of osteoclast differentiation and that it may have relevance to the pathogenesis of PDB and other metabolic bone diseases associated with osteoclast activation.<\/jats:p>","DOI":"10.3390\/cells12070981","type":"journal-article","created":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T04:31:05Z","timestamp":1679632265000},"page":"981","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Aged G Protein-Coupled Receptor Kinase 3 (Grk3)-Deficient Mice Exhibit Enhanced Osteoclastogenesis and Develop Bone Lesions Analogous to Human Paget\u2019s Disease of Bone"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4171-6836","authenticated-orcid":false,"given":"Emily M.","family":"Rabjohns","sequence":"first","affiliation":[{"name":"Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rishi R.","family":"Rampersad","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3401-9004","authenticated-orcid":false,"given":"Arin","family":"Ghosh","sequence":"additional","affiliation":[{"name":"College of Arts and Sciences, Duke University, Durham, NC 27510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katlyn","family":"Hurst","sequence":"additional","affiliation":[{"name":"College of Arts and Sciences, Duke University, Durham, NC 27510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3107-5545","authenticated-orcid":false,"given":"Amanda M.","family":"Eudy","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime M.","family":"Brozowski","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Ho","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinshi","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Texas Southwestern, Dallas, TX 75390, USA"},{"name":"Scottish Rite Hospital, Dallas, TX 75219, USA"},{"name":"Department of Orthopedics, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Mirando","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Gladman","sequence":"additional","affiliation":[{"name":"Pratt School of Engineering, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L.","family":"Bowser","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5972-4009","authenticated-orcid":false,"given":"Kathryn","family":"Berg","sequence":"additional","affiliation":[{"name":"Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachin","family":"Wani","sequence":"additional","affiliation":[{"name":"Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2804-7586","authenticated-orcid":false,"given":"Stuart H.","family":"Ralston","sequence":"additional","affiliation":[{"name":"Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3165-267X","authenticated-orcid":false,"given":"Matthew J.","family":"Hilton","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4067-5363","authenticated-orcid":false,"given":"Teresa K.","family":"Tarrant","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USA"},{"name":"Durham Veterans Hospital, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0140-6736(08)61035-1","article-title":"Pathogenesis and management of Paget\u2019s disease of 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Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1359\/jbmr.070333","article-title":"Identification of sex-specific associations between polymorphisms of the osteoprotegerin gene, TNFRSF11B, and Paget\u2019s disease of bone","volume":"22","author":"Beyens","year":"2007","journal-title":"J. Bone Miner. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1172\/JCI28267","article-title":"Mutation of the sequestosome 1 (p62) gene increases osteoclastogenesis but does not induce Paget disease","volume":"117","author":"Kurihara","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2734","DOI":"10.1093\/hmg\/ddr172","article-title":"A point mutation in the ubiquitin-associated domain of SQSMT1 is sufficient to cause a Paget\u2019s disease-like disorder in mice","volume":"20","author":"Daroszewska","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"dmm035576","DOI":"10.1242\/dmm.035576","article-title":"Zoledronic acid prevents pagetic-like lesions and accelerated bone loss in the p62(P394L) mouse model of Paget\u2019s disease","volume":"11","author":"Daroszewska","year":"2018","journal-title":"Dis. Model. Mech."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1016\/j.celrep.2015.09.071","article-title":"Optineurin Negatively Regulates Osteoclast Differentiation by Modulating NF-kappaB and Interferon Signaling: Implications for Paget\u2019s Disease","volume":"13","author":"Obaid","year":"2015","journal-title":"Cell Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41418-019-0341-6","article-title":"Global deletion of Optineurin results in altered type I IFN signaling and abnormal bone remodeling in a model of Paget\u2019s disease","volume":"27","author":"Wong","year":"2020","journal-title":"Cell Death Differ."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"eade6998","DOI":"10.1126\/sciadv.ade6998","article-title":"Optineurin regulates NRF2-mediated antioxidant response in a mouse model of Paget\u2019s disease of bone","volume":"9","author":"Hu","year":"2023","journal-title":"Sci. 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