Journal
BONE
Volume 67, Issue -, Pages 166-174Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.bone.2014.07.003
Keywords
Zoledronic acid; p38 MAPK; beta-Catenin; Bcl-xL; Osteoclast precursor; Osteoporosis
Categories
Funding
- National Science Council, Taiwan [NSC 96-2320-B-006-018-MY3, NSC 101-2314-B-006-009-MY3]
Ask authors/readers for more resources
The nitrogen-containing bisphosphonate zoledronic acid (ZA) induces apoptosis in osteoclasts and inhibits osteoclast-mediated bone resorption. It is widely used to treat osteoporosis. However, some patients are less responsive to ZA treatment, and the mechanisms of resistance are still unclear. Here, we identified that murine osteoclast precursors may develop resistance to ZA-induced apoptosis. These resistant cells survived the apoptotic effect of ZA following an increase in anti-apoptotic Bcl-xL. Pharmacologically inhibiting Bcl-xL facilitated ZA-induced apoptosis. Treatment with ZA activated p38 MAPK, increasing Bcl-xL expression and cell survival. Nuclear import of beta-catenin regulated by p38 MAPK determined Bcl-xL mRNA expression and cell survival in response to ZA. ZA also inactivated glycogen synthase kinase (GSK)-3 beta, a negative upstream regulator of beta-catenin, in a p38 MAPK-mediated manner. Synergistic pharmacological inhibition of p38 MAPK with ZA attenuated receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and facilitated ZA-induced apoptosis. These results demonstrate that elevated Bcl-xL expression mediated by p38 MAPK-regulated GSK-3 beta/beta-catenin signaling is required for cell survival of ZA-induced apoptosis in both osteoclast precursors and osteoclasts. Finally, we demonstrated that inhibiting p38 MAPK-mediated pathway enhanced ZA effect on increasing the bone mineral density of ovariectomized mice. This result suggests that targeting these pathways may represent a potential therapeutic strategy. (C) 2014 Elsevier Inc. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available