Activation of ROS/MAPK s /NF‐ κ B/NLRP3 and inhibition of efferocytosis in osteoclast‐mediated diabetic osteoporosis

Abstract

Diabetes mellitus (DM) affects bone metabolism and leads to osteoporosis; however, its pathogenetic mechanisms remain unknown. We found that high glucose (HG) conditions induced the production of reactive oxygen species (ROS) and the expression of proteins related to MAPKs [phosphorylated (p)‐ERK, p‐JNK, and p‐p38], NF‐ κ B(NF‐ κ B, p‐IαB, and IKK), and NACHT‐LRR‐PYD domains‐containing protein 3 (NALP3) (NLRP3) [apoptosis‐associated speck‐like protein containing a caspase activation and recruitment domain (ASC), caspase‐1, IL‐18, IL‐1β, and NLRP3] in osteoclasts (OCs) in vitro . Further analysis showed that in HG‐induced OCs, ROS is an upstream signal for MAPKs, NF‐ κ B, and the NLRP3 inflammasome. Moreover, MAPKs mediated the activation of NF‐ κ B and NLRP3, whereas NF‐ κ B up‐regulated the NLRP3 inflammasome response. Interestingly, HG inducement enhanced the bone resorption of OCs but inhibited their efferocytosis, whereas insulin and lipoxin A4 (4) treatment reversed this phenomenon. In streptozotocin‐induced diabetic rats in vivo , the numbers and the bone‐resorption capacity of OCs as well as the serum levels of TRACP‐5b were significantly increased, and the expression of MAPK‐, NF‐ κ B‐, and NLRP3 inflammasome‐related proteins in the proximal tibia were also significantly elevated; however, treatment with insulin and LXA4 reversed this elevation. Together, these results demonstrated that the activation of ROS/MAPK s /NF‐ κ B/NLRP3 and the inhibition of efferocytosis in OCs are the main causes of osteoporosis in DM.—An, Y., Zhang, H., Wang, C., Jiao, F., Xu, H., Wang, X., Luan, W., Ma, F., Ni, L., Tang, X., Liu, M., Guo, W., Yu, L. Activation of ROS/MAPK s /NF‐ κ B/NLRP3 and inhibition of efferocytosis in osteoclast‐mediated diabetic osteoporosis. FASEB J. 33, 12515–12527 (2019). www.fasebj.org