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 (DHA). FFA4 knockout (Ffar4-/-) and wild-type mice exhibited similar bone masses when fed on a normal diet. Since fat-1 transgenic (fat-1Tg+) mice endogenously converting n-6 to n-3 FAs contain high n-3 FA levels, we crossed Ffar4-/- and fat-1Tg+ mice over 2 generations to generate 4 genotypes of mice littermates: Ffar4+/+;fat-1Tg-, Ffar4+/+;fat-1Tg+, Ffar4-/-;fat-1Tg-, and Ffar4-/-;fat-1Tg+. ...