{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T21:50:28Z","timestamp":1792619428640,"version":"4.5.0"},"reference-count":111,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K23573"],"award-info":[{"award-number":["24K23573"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K02830"],"award-info":[{"award-number":["25K02830"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Osteoclastogenesis\u2014the activation and differentiation of osteoclasts\u2014is one of the pivotal processes of bone remodeling and is regulated by RANKL\/RANK signaling, the decoy function of osteoprotegerin (OPG), and a cascade of pro- and anti-inflammatory cytokines. The disruption of this balance leads to pathological bone loss in diseases such as osteoporosis and rheumatoid arthritis. FFAR4 (Free Fatty Acid Receptor 4), a G protein-coupled receptor for long-chain omega-3 fatty acids, has been confirmed as a key mediator of metabolic and anti-inflammatory effects. This review focuses on how FFAR4 acts as the selective receptor for the omega-3 fatty acid docosahexaenoic acid (DHA). It activates two divergent signaling pathways. The G\u03b1q-dependent cascade facilitates intracellular calcium mobilization and ERK1\/2 activation. Meanwhile, \u03b2-arrestin-2 recruitment inhibits NF-\u03baB. These collective actions reshape the cytokine environment. In macrophages, DHA\u2013FFAR4 signaling lowers the levels of TNF-\u03b1, interleukin-6 (IL-6), and IL-1\u03b2 while increasing IL-10 secretion. Consequently, the activation of NFATc1 and NF-\u03baB p65 is profoundly suppressed under TNF-\u03b1 or RANKL stimulation. Additionally, DHA modulates the RANKL\/OPG axis in osteoblastic cells by suppressing RANKL expression, thereby reducing osteoclast differentiation in an inflammatory mouse model.<\/jats:p>","DOI":"10.3390\/molecules30153180","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T16:16:10Z","timestamp":1753805770000},"page":"3180","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Docosahexaenoic Acid Inhibits Osteoclastogenesis via FFAR4-Mediated Regulation of Inflammatory Cytokines"],"prefix":"10.3390","volume":"30","author":[{"given":"Jinghan","family":"Ma","sequence":"first","affiliation":[{"name":"Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3249-4247","authenticated-orcid":false,"given":"Hideki","family":"Kitaura","sequence":"additional","affiliation":[{"name":"Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumitoshi","family":"Ohori","sequence":"additional","affiliation":[{"name":"Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aseel","family":"Marahleh","sequence":"additional","affiliation":[{"name":"Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai 980-8575, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8940-4979","authenticated-orcid":false,"given":"Ziqiu","family":"Fan","sequence":"additional","affiliation":[{"name":"Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8053-0858","authenticated-orcid":false,"given":"Angyi","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Narita","sequence":"additional","affiliation":[{"name":"Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kou","family":"Murakami","sequence":"additional","affiliation":[{"name":"Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyasu","family":"Kanetaka","sequence":"additional","affiliation":[{"name":"Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan"},{"name":"Division of Advanced Dental Science and Technology, Graduate School of Biomedical Engineering, Tohoku University, 6-6-12, Aramaki Aza Aoba Aoba-ku, Sendai 980-8579, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s00418-018-1636-2","article-title":"Recent Advances in Osteoclast Biology","volume":"149","author":"Ono","year":"2018","journal-title":"Histochem. 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