{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:31:53Z","timestamp":1786977113571,"version":"build-2736575974"},"reference-count":38,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T00:00:00Z","timestamp":1671062400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009945","name":"Merck KGaA","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009945","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To preclinically characterize a mutant form of growth and differentiation factor 5, R399E, with reduced osteogenic properties as a potential disease\u2010modifying osteoarthritis (OA) drug.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cartilage, synovium, and meniscus samples from patients with OA were used to evaluate anabolic and antiinflammatory properties of R399E. In the rabbit joint instability model, 65 rabbits underwent transection of the anterior cruciate ligament plus partial meniscectomy. Three intraarticular (IA) R399E doses were administered biweekly 6 times, and static incapacitance was determined to assess joint pain. OA was evaluated 13\u2009weeks after surgery. In sheep, medial meniscus transection was performed to induce OA, dynamic weight bearing was measured in\u2010life, and OA was assessed after 13\u2009weeks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Intermittent exposure to R399E (1 week per month) was sufficient to induce cell proliferation and release of anabolic markers in 3\u2010dimensional chondrocyte cultures. R399E also inhibited the release of interleukin\u20101\u03b2 (IL\u20101\u03b2), IL\u20106, and prostaglandin E\n                      <jats:sub>2<\/jats:sub>\n                      from cartilage with synovium, meniscal cell, and synoviocyte cultures. In rabbits, the mean difference (95% confidence interval [95% CI]) in weight bearing for R399E compared to vehicle was \u22125.8 (95% confidence interval [95% CI] \u22129.54, \u22122.15), \u22127.2 (95% CI \u221210.93, \u22123.54), and\u2009\u22127.7 (95% CI \u221211.49, \u22123.84) for the 0.6, 6, and 60 \u03bcg doses, respectively, 6 hours after the first IA injection, and was statistically significant through the entire study for all doses. Cartilage surface structure improved with the 6\u2010\u03bcg dose. Structural and symptomatic improvement with the same dose was confirmed in the sheep model of OA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>R399E influences several pathologic processes contributing to OA, highlighting its potential as a disease\u2010modifying therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.42343","type":"journal-article","created":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T10:39:05Z","timestamp":1662115145000},"page":"375-386","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp>R399E<\/scp>\n                    , A Mutated Form of Growth and Differentiation Factor 5, for Disease Modification of Osteoarthritis"],"prefix":"10.1002","volume":"75","author":[{"given":"Anne","family":"Gigout","sequence":"first","affiliation":[{"name":"Merck Healthcare KGaA 64293  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Werkmann","sequence":"additional","affiliation":[{"name":"Merck Healthcare KGaA 64293  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Menges","sequence":"additional","affiliation":[{"name":"Merck Healthcare KGaA 64293  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Brenneis","sequence":"additional","affiliation":[{"name":"Merck Healthcare KGaA 64293  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Henson","sequence":"additional","affiliation":[{"name":"Division of Trauma and Orthopaedic Surgery University of Cambridge  Cambridge 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