{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:29:51Z","timestamp":1792794591900,"version":"4.5.0"},"reference-count":50,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T00:00:00Z","timestamp":1658188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"NIH NIAMS","doi-asserted-by":"publisher","award":["R01 AR071968"],"award-info":[{"award-number":["R01 AR071968"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"NIH NIAMS","doi-asserted-by":"publisher","award":["R01 DK121327"],"award-info":[{"award-number":["R01 DK121327"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ANRF Arthritis Research Grant","award":["R01 AR071968"],"award-info":[{"award-number":["R01 AR071968"]}]},{"name":"ANRF Arthritis Research Grant","award":["R01 DK121327"],"award-info":[{"award-number":["R01 DK121327"]}]},{"DOI":"10.13039\/100000062","name":"NIH NIDDK","doi-asserted-by":"publisher","award":["R01 AR071968"],"award-info":[{"award-number":["R01 AR071968"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"NIH NIDDK","doi-asserted-by":"publisher","award":["R01 DK121327"],"award-info":[{"award-number":["R01 DK121327"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The G-protein-coupled receptor kinase 2 (GRK2) is an important regulator of inflammation and pathological macrophage phenotype in a variety of diseases. We hypothesize that G\u03b2\u03b3-GRK2 signaling promotes the early inflammatory response and chondrocyte loss in osteoarthritis (OA). Using the destabilization of the medial meniscus (DMM) model in 12-week-old male C57BL\/6 mice, we determined the role of G\u03b2\u03b3-GRK2 signaling in synovitis, macrophage activation, and OA development. We achieved G\u03b2\u03b3-GRK2 inhibition at the time of DMM by administering the G\u03b2\u03b3 inhibitor \u201cgallein\u201d and the GRK2 inhibitor \u201cparoxetine\u201d daily, starting from 2 days before DMM surgery, for a duration of 1 or 12 weeks. Synovial and cartilage structural changes were evaluated by histomorphometry, and molecular events and macrophage activation were examined. We studied the direct role of G\u03b2\u03b3-GRK2 in synovitis and macrophage activation in vitro using SW982 and THP1 cells. Continuous G\u03b2\u03b3-GRK2 inhibition initiated at the time of DMM attenuated OA development and decreased chondrocyte loss more effectively than delayed treatment. GRK2 expression and the M1 macrophage phenotype were elevated in the inflamed synovium, while early gallein and paroxetine treatment for 1 and 12 weeks following DMM resulted in their reduction and an upregulated M2 macrophage phenotype. In vitro experiments showed that G\u03b2\u03b3-GRK2 inhibition attenuated synoviocyte inflammation and the M1 phenotype. We show that early G\u03b2\u03b3-GRK2 inhibition is of higher therapeutic efficacy in OA than delayed inhibition, as it prevents OA development by inhibiting the early inflammatory response.<\/jats:p>","DOI":"10.3390\/ijms23147933","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T05:37:53Z","timestamp":1658209073000},"page":"7933","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Early G\u03b2\u03b3-GRK2 Inhibition Ameliorates Osteoarthritis Development by Simultaneous Anti-Inflammatory and Chondroprotective Effects"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1511-7810","authenticated-orcid":false,"given":"Vengadeshprabhu","family":"Karuppagounder","sequence":"first","affiliation":[{"name":"Center for Orthopaedic Research and Translational Science (CORTS), Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA"},{"name":"Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Pinamont","sequence":"additional","affiliation":[{"name":"Center for Orthopaedic Research and Translational Science (CORTS), Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA"},{"name":"Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2968-5205","authenticated-orcid":false,"given":"Natalie","family":"Yoshioka","sequence":"additional","affiliation":[{"name":"Center for Orthopaedic Research and Translational Science (CORTS), Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA"},{"name":"Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reyad","family":"Elbarbary","sequence":"additional","affiliation":[{"name":"Center for Orthopaedic Research and Translational Science (CORTS), Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA"},{"name":"Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2408-4061","authenticated-orcid":false,"given":"Fadia","family":"Kamal","sequence":"additional","affiliation":[{"name":"Center for Orthopaedic Research and Translational Science (CORTS), Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA"},{"name":"Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1136\/annrheumdis-2018-213450","article-title":"Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2","volume":"77","author":"Zhang","year":"2018","journal-title":"Ann. 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