Endocrinology 2016 07 4;157(7):2621-35. Epub 2016 May 4.
Department of Endocrinology and Metabolism (S.H.A.), Inha University Hospital, Inha University School of Medicine, Incheon 402-751, South Korea; Asan Institute for Life Sciences (S.-Y.P., J.-E.B., S.-Youn.L., W.-.Y.B., S.-Young.L., Y.-S.L.) and Biomedical Research Center (H.J.Y.) and Division of Endocrinology and Metabolism (H.K., S.H.L., B.-J.K., J.-M.K.), Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea; Molecular Inflammation Research Center for Aging Intervention and College of Pharmacy (D.-S.I.), Pusan National University, Busan 609-735, South Korea; and UConn Center on Aging (S.-K.L.), University of Connecticut Health Center, Farmington, Connecticut 06030-1601.
Free fatty acid receptor 4 (FFA4) has been reported to be a receptor for n-3 fatty acids (FAs). Although n-3 FAs are beneficial for bone health, a role of FFA4 in bone metabolism has been rarely investigated. We noted that FFA4 was more abundantly expressed in both mature osteoclasts and osteoblasts than their respective precursors and that it was activated by docosahexaenoic acid. FFA4 knockout (Ffar4(-/-)) and wild-type mice exhibited similar bone masses when fed a normal diet. Because fat-1 transgenic (fat-1(Tg+)) mice endogenously converting n-6 to n-3 FAs contain high n-3 FA levels, we crossed Ffar4(-/-) and fat-1(Tg+) mice over two generations to generate four genotypes of mice littermates: Ffar4(+/+);fat-1(Tg-), Ffar4(+/+);fat-1(Tg+), Ffar4(-/-);fat-1(Tg-), and Ffar4(-/-);fat-1(Tg+). Female and male littermates were included in ovariectomy- and high-fat diet-induced bone loss models, respectively. Female fat-1(Tg+) mice decreased bone loss after ovariectomy both by promoting osteoblastic bone formation and inhibiting osteoclastic bone resorption than their wild-type littermates, only when they had the Ffar4(+/+) background, but not the Ffar4(-/-) background. In a high-fat diet-fed model, male fat-1(Tg+) mice had higher bone mass resulting from stimulated bone formation and reduced bone resorption than their wild-type littermates, only when they had the Ffar4(+/+) background, but not the Ffar4(-/-) background. In vitro studies supported the role of FFA4 as n-3 FA receptor in bone metabolism. In conclusion, FFA4 is a dual-acting factor that increases osteoblastic bone formation and decreases osteoclastic bone resorption, suggesting that it may be an ideal target for modulating metabolic bone diseases.