Acetaminophen reduces osteoprotegerin synthesis stimulated by PGE₂ and PGF_2α in osteoblasts: attenuation of SAPK/JNK but not p38 MAPK or p44/p42 MAPK

Abstract

Acetaminophen is one of the most widely used analgesic and antipyretic medicines, whose long-period use has reportedly been associated with an increased risk of bone fracture. However, the mechanism underlying this undesired effect remains to be investigated. The homeostatic control of bone tissue depends on the interaction between osteoblasts and osteoclasts. Osteoprotegerin produced by osteoblasts is known to play an essential role in suppressing osteoclast induction. We have previously reported that prostaglandin (PG) E 2 and PGF 2α induce osteoprotegerin synthesis through p38 mitogen-activated protein kinase (MAPK), p44/p42 MAPK and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effects of acetaminophen on the osteoprotegerin synthesis induced by PGE 2 and PGF 2α in MC3T3-E1 cells. Acetaminophen significantly suppressed the osteoprotegerin release stimulated by PGE 2 and PGF 2α . The PGE 2 -induced expression of osteoprotegerin mRNA was also reduced by acetaminophen. Acetaminophen markedly downregulated the phosphorylation of SAPK/JNK stimulated by PGE 2 and PGF 2α , but not those of p38 MAPK or p44/p42 MAPK. SP600125, an inhibitor of SAPK/JNK, suppressed the levels of PGE 2 -and PGF 2α -upregulated osteoprotegerin mRNA expression. Taken together, these results strongly suggest that acetaminophen reduces the PGE 2 -and PGF 2α -stimulated synthesis of osteoprotegerin in osteoblasts, and that the suppressive effect is exerted via attenuation of SAPK/JNK. These findings provide a molecular basis for the possible effect of acetaminophen on bone tissue metabolism.

Revisiting Resveratrol as an Osteoprotective Agent: Molecular Evidence from In Vivo and In Vitro Studies

“…However, PGE2 and PGF2α are now recognised as bone remodelling mediators that regulate a wide range of intracellular signalling pathways in osteoblasts [95,96]. A previous study reported that PGE2 and PGF2α induced IL-6 secretion via activation of p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in MC3T3-E1 cells [97]. According to Yamamoto et al [98] and Kuroyanagi et al [99], RSV markedly reduced the PGE2 and PGF2α-stimulated OPG synthesis through the inhibition of p44/p42 MAP kinase, p38 MAP kinase, and SAPK/JNK in osteoblasts.…”