Celecoxib inhibits osteoblast differentiation independent of cyclooxygenase activity

Abstract

SummaryNon-steroidal anti-inflammatory drugs (NSAIDs) exert their effects primarily by inhibiting the activity of cyclooxygenase (COX), thus suppressing prostaglandin synthesis.Some NSAIDs are known to perform functions other than pain control, such as suppressing tumour cell growth, independent of their COX-inhibiting activity. To identify NSAIDs with COX-independent activity, we examined various NSAIDs for their ability to inhibit osteoblastic differentiation using the mouse pre-osteoblast cell line MC3T3-E1. Only celecoxib and valdecoxib strongly inhibited osteoblastic differentiation, and this effect was not correlated with COX-inhibiting activity. Moreover, K E Y W O R D Sbone morphogenetic protein-2, celecoxib, cyclooxygenase, non-steroidal anti-inflammatory drugs, osteoblast, Smad1/5 signalling pathway

Emerging evidence that adaptive bone formation inhibition by non-steroidal anti-inflammatory drugs increases stress fracture risk

“…50 Moreover, celecoxib, valdecoxib, and a non-COX-inhibiting celecoxib derivative demonstrated the ability to suppress osteoblast differentiation, suggesting NSAIDs possess a mechanism(s) of action independent of COX inhibition. 53 Additional studies report that NSAIDs decrease alkaline phosphatase and type 1 collagen levels as well as the size of mineralization nodules within cell cultures. 51 Together, these reports suggest that NSAIDs may reduce the abundance of osteoblasts as well as their ability to produce new bone matrix.…”

Effect of Non-Steroidal Anti-Inflammatory Drugs on Bone Healing and Osseointegration: the Need for large Scale Human Clinical Trials

“…However, it is worth noting that there is an increasing number of reports that suggest the effects selective COX-2 inhibitors are detrimental to bone or facture healing [31][32][33]. It has been suggested that selective COX-2 inhibitors such as celecoxib inhibit bone morphogenetic protein 2 (BMP2) regulated osteoblast differentiation independent of COX activity [34], therefore, caution should be used when prescribing selective COX-2 inhibitors.…”

Effects of Therapeutic Doses of Celecoxib on Several Physiological Parameters of Cultured Human Osteoblasts

“…The finding that celecoxib at 0.75, 2, or 5 µM (within the therapeutic range) has no effect on osteoblast growth is in line with previously published results. For instance, proapoptotic effects were observed after the treatment of MG63 human osteoblast cells with celecoxib at a dose of 50 µM but not at a dose of 2 or 10 µM 20, and no changes in the proliferation or viability of the murine pre-osteoblastic cell line MC3T3-E1 were observed after treatment with celecoxib at a dose of 20 µM 21. However, celecoxib at doses of 0.1 or 1 µM was found to inhibit cell proliferation and arrest the cell cycle in G0/G1 phase in cultured human osteoblasts 4 and in mesenchymal cells derived from mouse bone marrow 22.…”

“…Although no effect on osteoblast growth or antigenic profile was observed, celecoxib doses of 2 and 5 µM inhibited the gene expression of differentiation markers RUNX2 and OSC but not ALP or OSX. Matsuyama et al 21 reported that celecoxib doses between 0.02 and 20 µM inhibit osteoblast differentiation in the MC3T3-E1 line but do not alter cell viability, indicating that negative effects on bone tissue at doses above 0.02 μM may be attributable to the inhibition of osteoblast differentiation. Nagano et al 32 found that 50 µM celecoxib can inhibit the expression of RUNX2 mRNA in the same cell line (MC3T3-E1).…”