Docosahexaenoic Acid Inhibits Osteoclastogenesis via FFAR4-Mediated Regulation of Inflammatory Cytokines
Osteoclastogenesis—the activation and differentiation of osteoclasts—is 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 t...
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2025-07-01
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| author | Jinghan Ma Hideki Kitaura Fumitoshi Ohori Aseel Marahleh Ziqiu Fan Angyi Lin Kohei Narita Kou Murakami Hiroyasu Kanetaka |
| author_facet | Jinghan Ma Hideki Kitaura Fumitoshi Ohori Aseel Marahleh Ziqiu Fan Angyi Lin Kohei Narita Kou Murakami Hiroyasu Kanetaka |
| author_sort | Jinghan Ma |
| collection | DOAJ |
| description | Osteoclastogenesis—the activation and differentiation of osteoclasts—is 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 Gαq-dependent cascade facilitates intracellular calcium mobilization and ERK1/2 activation. Meanwhile, β-arrestin-2 recruitment inhibits NF-κB. These collective actions reshape the cytokine environment. In macrophages, DHA–FFAR4 signaling lowers the levels of TNF-α, interleukin-6 (IL-6), and IL-1β while increasing IL-10 secretion. Consequently, the activation of NFATc1 and NF-κB p65 is profoundly suppressed under TNF-α 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. |
| format | Article |
| id | doaj-art-db927dfd1a5c4cd7b77c96a6934f4ac5 |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-07-01 |
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| series | Molecules |
| spelling | doaj-art-db927dfd1a5c4cd7b77c96a6934f4ac52025-08-20T03:02:49ZengMDPI AGMolecules1420-30492025-07-013015318010.3390/molecules30153180Docosahexaenoic Acid Inhibits Osteoclastogenesis via FFAR4-Mediated Regulation of Inflammatory CytokinesJinghan Ma0Hideki Kitaura1Fumitoshi Ohori2Aseel Marahleh3Ziqiu Fan4Angyi Lin5Kohei Narita6Kou Murakami7Hiroyasu Kanetaka8Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, JapanDivision of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, JapanDivision of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, JapanFrontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai 980-8575, Miyagi, JapanDivision of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, JapanDivision of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, JapanDivision of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, JapanDivision of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, JapanDivision of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, JapanOsteoclastogenesis—the activation and differentiation of osteoclasts—is 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 Gαq-dependent cascade facilitates intracellular calcium mobilization and ERK1/2 activation. Meanwhile, β-arrestin-2 recruitment inhibits NF-κB. These collective actions reshape the cytokine environment. In macrophages, DHA–FFAR4 signaling lowers the levels of TNF-α, interleukin-6 (IL-6), and IL-1β while increasing IL-10 secretion. Consequently, the activation of NFATc1 and NF-κB p65 is profoundly suppressed under TNF-α 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.https://www.mdpi.com/1420-3049/30/15/3180docosahexaenoic acidFFAR4osteoclastbone metabolism |
| spellingShingle | Jinghan Ma Hideki Kitaura Fumitoshi Ohori Aseel Marahleh Ziqiu Fan Angyi Lin Kohei Narita Kou Murakami Hiroyasu Kanetaka Docosahexaenoic Acid Inhibits Osteoclastogenesis via FFAR4-Mediated Regulation of Inflammatory Cytokines Molecules docosahexaenoic acid FFAR4 osteoclast bone metabolism |
| title | Docosahexaenoic Acid Inhibits Osteoclastogenesis via FFAR4-Mediated Regulation of Inflammatory Cytokines |
| title_full | Docosahexaenoic Acid Inhibits Osteoclastogenesis via FFAR4-Mediated Regulation of Inflammatory Cytokines |
| title_fullStr | Docosahexaenoic Acid Inhibits Osteoclastogenesis via FFAR4-Mediated Regulation of Inflammatory Cytokines |
| title_full_unstemmed | Docosahexaenoic Acid Inhibits Osteoclastogenesis via FFAR4-Mediated Regulation of Inflammatory Cytokines |
| title_short | Docosahexaenoic Acid Inhibits Osteoclastogenesis via FFAR4-Mediated Regulation of Inflammatory Cytokines |
| title_sort | docosahexaenoic acid inhibits osteoclastogenesis via ffar4 mediated regulation of inflammatory cytokines |
| topic | docosahexaenoic acid FFAR4 osteoclast bone metabolism |
| url | https://www.mdpi.com/1420-3049/30/15/3180 |
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