Inhibition of Cdk5 Ameliorates Skeletal Bone Loss in Glucocorticoid-Treated Mice

Abstract

Glucocorticoids (GCs) are widely used to treat inflammatory diseases. However, their long-term use leads to glucocorticoid-induced osteoporosis, increasing morbidity and mortality. Both anabolic and anti-resorptive drugs are used to counteract GC-induced bone loss, however, they are expensive and/or have major side effects. Therefore, identifying new targets for cost-effective, small-molecule inhibitors is essential. We recently identified cyclin-dependent kinase 5 (Cdk5) as a suppressor of osteoblast differentiation and showed that its inhibition with roscovitine promoted osteoblastogenesis, thus improving the skeletal bone mass and fracture healing. Here, we assessed whether Cdk5 knockdown or inhibition could also reverse the GC-mediated suppression of osteoblast differentiation, bone loss, and fracture healing. We first demonstrated that Cdk5 silencing abolished the dexamethasone (Dex)-induced downregulation of alkaline phosphatase (Alp) activity, osteoblast-specific marker gene expression (Runx2, Sp7, Alpl, and Bglap), and mineralization. Similarly, Cdk5 inhibition rescued Dex-induced suppression of Alp activity. We further demonstrated that Cdk5 inhibition reversed prednisolone (Pred)-induced bone loss in mice, due to reduced osteoclastogenesis rather than improved osteoblastogenesis. Moreover, we revealed that Cdk5 inhibition failed to improve Pred-mediated impaired fracture healing. Taken together, we demonstrated that Cdk5 inhibition with roscovitine ameliorated GC-mediated bone loss but did not reverse GC-induced compromised fracture healing in mice.

Allolobophora caliginosa coelomic fluid and extract alleviate glucocorticoid-induced osteoporosis in mice by suppressing oxidative stress and regulating osteoblastic/osteoclastic-related markers

“…Glucocorticoids (GCs) are widely utilized to treat various systemic disorders and are important anti-inflammatory and immunosuppressive agents 1 . In contrast, long-term use of GCs promotes bone loss by destroying osteocytes and osteoblasts and increasing reactive species generation 2 . The synthetic long-acting GC, dexamethasone (DEX), causes disturbance in bone homeostasis 3 .…”