Involvement of ERK5 signaling pathway in osteoporosis development in mice / 中国组织工程研究

ABSTRACT

BACKGROUND: Although extracellular signal-regulated kinase 5 (ERK5) is an essential transducer of external signals for osteoblasts growth, differentiation, and survival, the effects of ERK5 signaling on bone homeostasis in vivo have not yet been described. OBJECTIVE: To elucidate whether the inhibition of ERK5 activity and its downstream targets by XMD8-92 results in osteoporosis and aggravates dexamethasone-induced osteoporosis. METHODS: In vivo experiment A mouse model of osteoporosis was induced by dexamethasone. There were four groups blank control group (PBS); XMD8-92 group (50 mg/kg); dexamethasone group (50 mg/kg); XMD8-92+dexamethasone group (50 mg/kg XMD8-92 plus 50 mg/kg dexamethasone). Administration was done for 5 continuous weeks. Cell experiment There were four groups blank control group; XMD8-92 group (5 μmol/L); dexamethasone group (10×10-6 mol/L); XMD8-92+dexamethasone group (treatment with 5 μmol/L XMD8-92 followed by 10×10-6 mol/L dexamethasone). Cells were incubated for 1 hour. In addition, ERK5 activation was induced using epidermal growth factor. ERK5 activity in mice and MC3T3-E1 cells were detected. We further detected bone mass, bone architecture and mechanical stress of the trabecular bone, measured the expression of receptor activator of nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) and observed the roles of XMD8-92 in osteoblast proliferation and apoptosis. The study protocol was approved by the Ethics Committee of the Second Hospital of Lanzhou University (No. 2016-D44). RESULTS AND CONCLUSION: XMD8-92 could block ERK5 phosphorylation, change the architecture of the trabecular bone, reduce bone mass and aggravate dexamethasone-induced osteoporosis. XMD8-92 could significantly reduce the biomechanical properties of bone tissues in mice. XMD8-92 could up-regulate RANKL/OPG rate, lower osteoblasts vitality by inhibiting Cyclin B1 and CDK1 expression, and promote osteoblast apoptosis by up-regulating the expression of FasL. The novel findings suggest that ERK5 activity plays an important role in maintenance of bone mass, and altered ERK5 activation in disease conditions such as osteoporosis or dexamethasone-induced osteoporosis should be considered as a potential mechanism for abnormal bone homeostasis.