화학공학소재연구정보센터
Biochemical and Biophysical Research Communications, Vol.496, No.3, 967-974, 2018
Cereblon (CRBN) deletion reverses streptozotocin induced diabetic osteoporosis in mice
Diabetes mellitus is a major cause to induce osteoporosis. Though the pathogenesis of osteoporosis progression has been well investigated, its still not fully understood. Recently, cereblon (CRBN) was considered as a negative modulator of adenosine monophosphate-activated protein kinase (AMPK) in vitro and in vivo. Here, we presented results indicating that CRBN could effectively regulate osteoporosis development. In STZ-induced wild type (WT) mice with diabetes, the osteoclasts were highly increased along with the deterioration of bone structure. However, CRBN knockout (KO) reduced blood glucose the levels and attenuated insulin resistance. What's more, CRBN ablation suppressed osteoclast differentiation and rescued diabetic bone loss in vivo, accompanied with decreased receptor activator of NF-kB ligand (RANKL), RANKL/osteoprotegerin (OPG), and tartrate-resistant acid phosphatase (TRAP) levels, as well as improved AMP-activated kinase (AMPK) alpha/acetyl-CoA carboxylase (ACC)alpha activation. In vitro, suppressing CRBN expression could reduce RANKL-induced osteoclastogenesis, supported by the reduction of TRAP-positive cells. CRBN knockdown (KD) obviously reduced RANKL-induced activity of I kappa B alpha/nuclear factor-kappa B (NF-kappa B) pathway. In addition, osteoclast-specific genes expression levels stimulated by RANKL were also decreased by CRBN silence. More importantly, CRBN blockage increased phosphorylated AMPK-a and ACC-alpha expressions in RANKL-incubated cells. However, these processes could be abolished by suppressing AMPK-alpha with its inhibitor, Compound C. Collectively, our data suggested that CRBN is a potential treatment option against diabetes-induced osteolytic bone disease. (C) 2018 Published by Elsevier Inc.