Activation of Dusp14 protects against osteoclast generation and bone loss by regulating AMPKα-dependent manner（破骨细胞生成和骨丢失研究）
Lei Hong 1 , Jiangbo Ai 2 , Danian Ma 3
Affiliations
- 1 Department of Orthopedic Surgery, First Affiliated Hospital of PLA General Hospital, Beijing, 100048, China.
- 2 Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
- 3 Department of Orthopedics, Xuyi County People’s Hospital, Huai’an, 211700, China. Electronic address: gavinle1977@foxmail.com.
Abstract
Osteoporosis is a progressive systematic skeletal disorder featured by decreased bone and enhanced risk of fracture due to an uncoupling of bone resorption. Chronic inflammatory response plays an essential role in osteoporosis progression. Unfortunately, the pathogenesis that contributes to osteoporosis still remains unclear. Dual-specificity phosphatase 14 (Dusp14, also known as MKP6) is a MAP kinase phosphatase, and has important roles in regulating various cellular processes. In the study, we attempted to explore the effects of Dusp14 on osteoporosis development. The results indicated that Dusp14 expression was decreased during osteoclast differentiation and that Dusp14 over-expression markedly alleviated osteoclast generation regulated by macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). In M-CSF/RANKL-treated bone marrow-derived cells (BMMs), promoting Dusp14 expression significantly alleviated inflammation and apoptosis by suppressing nuclear factor (NF)-κB and Caspase-3 signaling pathways, respectively. Furthermore, AMP-activated protein kinase (AMPK)-α activation was markedly increased by Dusp14 over-expression in M-CSF/RANKL-incubated BMMs. Importantly, we found that AMPKα blockage obviously abolished the role of Dusp14 in preventing osteoclasts differentiation at least partly via elevating M-CSF/RANKL-elicited inflammation and apoptosis. In vivo, magnesium silicate-induced inflammatory osteoporosis was obviously alleviated in Dusp14 transgenic (TG) mice. Taken together, we defined Dusp14 as an important molecular switch resulting in osteoporosis through an AMPKα-dependent manner.
Keywords: AMPKα; Apoptosis; Dusp14; Inflammation; Osteoporosis.