Cyclooxygenase-2 selective inhibition suppresses restoration of tibial trabecular bone formation in association with restriction of osteoblast maturation in skeletal reloading after hindlimb elevation of mice

Abstract

To clarify the role of cyclooxygenase-2 (COX-2) in acute recovery of trabecular bone in reloaded hindlimbs of tail-suspended mice, we administered a COX-2 selective inhibitor in the mice during the reloading period after unloading. Experiments were conducted on 140 male C57BL/6J mice (8 weeks old). They were divided into ground control (GC) and unloading by tail suspension (UL) groups. On day 7, Group GC was divided into Groups GC + Vehicle (Veh) and GC + Celecoxib (Cel), while Group UL mice were fed on the ground [reloading (RL)] after 7-day unloading and were then divided into Groups RL + Veh and RL + Cel. Bone histomorphometry, osteogenic cell development, and mRNA expression of osteogenic molecules were assessed. At 5 days after reloading, the increase of bone formation rate and the ratio of osteocalcin mRNA expression per CFU-f colony in Group RL + Cel were significantly decreased compared with those in Group RL + Veh, while alkaline phosphatase-positive (ALP +) CFU-f formation and the ratios of cbfa-1, osterix, and type 1 collagen mRNA expression per CFU-f colony increased to the same levels in both RL groups. At 14 days after reloading, decreased bone volume by unloading in RL + Veh recovered to the same level as that of GC + Veh, but that in RL + Cel did not recover completely. The increase of c -fos mRNA expression in bone marrow cells at 1, 24, and 48 h after reloading, osteocalcin mRNA at 6 h, and osterix mRNA at 24 h were suppressed by COX-2 inhibitor. These data indicate that the COX-2 selective inhibitor celecoxib suppresses the restoration of tibial trabecular bone formation and the acute recovery of trabecular bone. These actions are closely related to restriction of c- fos and osteocalcin mRNA expressions and osteoblast differentiation in bone marrow cells.