Impaired bone resorption by lipopolysaccharide in vivo in mice deficient in the prostaglandin E receptor EP4 subtype

In a previous study we showed that the involvement of EP4 subtype of the pr ostaglandin E (PGE) receptor is crucial for lipopolysaccharide (LPS)-induce d osteoclast formation in vitro. The present study was undertaken to test w hether EP4 is actually associated with LPS-induced bone resorption in vivo. In wild-type (WT) mice, osteoclast formation in vertebrae and tibiae incre ased 5 days after systemic LPS injection, and urinary excretion of deoxypyr idinoline, a sensitive marker for bone resorption, statistically increased 10 days after injection. In EP4 knockout (KO) mice, however, LPS injection caused no significant changes in these parameters throughout the experiment . LPS exposure for 4 h strongly induced osteoclast differentiation factor ( ODF) mRNA expression in primary osteoblastic cells (POB) both from WT and E P4 KO mice, and this expression was not inhibited by indomethacin, suggesti ng prostaglandin (PG) independence. LPS exposure for 24 h further induced O DF expression in WT POB, but not in EP4 KO POB. Indomethacin partially inhi bited ODF expression in WT POB, but not in EP4 KO POB. These data suggest t hat ODF is induced both PG dependently and PG independently. LPS exposure f ar 24 h induced slightly greater osteoclastgenesis inhibitory factor (OCIF) mRNA expression in EP4 KO than in WT POB. These findings suggest that the reduced ODF expression and apparently increased OCIF expression also are re sponsible for the markedly reduced LPS-induced osteoclast formation in EP4 KO mice. Our results show that the EP4 subtype of the PGE receptor is invol ved in LPS-induced bone resorption in vivo also. Since LPS is considered to be largely involved in bacterially induced bone loss, such as in periodont itis and osteomyelitis, our study is expected to help broaden our understan ding of the pathophysiology of these conditions.