Cordycepin protected against the TNF-α-induced inhibition of osteogenic differentiation of human adipose-derived mesenchymal stem cells

Abstract

Cordycepin, 3'-deoxyadenosine, is an effective component isolated from the rare Chinese caterpillar fungus Cordyceps militaris. It exerts potent anti-inflammatory actions in different cell and animal models. However, its action remains unclear on the TNF-α-induced inhibition of osteogenic differentiation of adipose-derived mesenchymal stem cells (ADMSCs). In the present study, we demonstrated that cordycepin induced cell death at 20 and 40 μg/mL. Interestingly, 10 μg/mL cordycepin abrogated the cell death induced by 20 ng/mL TNF-α. Meanwhile, cordycepin exhibited a dosedependent regulation of the osteogenesis of human ADMSCs: it promoted the differentiation at 10 μg/mL, whereas inhibited differentiation at 40 μg/mL. Furthermore, we discovered that 10 μg/mL cordycepin protected against the TNF-α (induced inhibition of osteogenic differentiation of human ADMSCs. It was also revealed that 10 μg/mL cordycepin restored Runx2 and Osx mRNA levels, which were significantly inhibited by TNF-αduring osteogenesis. At the same time, we found that 10 μg/mL cordycepin suppressed TNF-α-activated NF-κB signaling, by inhibiting IκBα phosphorylation and subsequent p65 release and translocation into the cell nucleus. Of clinical interest, the present study revealed mechanisms involved in inflammatory cytokine-inhibited osteogenesis, and it highlights the potential of cordycepin to promote the osteogenesis of human ADMSCs in cell-based therapy for inflammatory bone diseases.

Cordycepin inhibits chondrocyte hypertrophy of mesenchymal stem cells through PI3K/Bapx1 and Notch signaling pathway

“…Based on the characteristics of cordycepin, we hypothesized that cordycepin might also have effect on cartilage metabolism. A previous study has shown that cordycepin has protection against inflammatory cytokine inhibition of osteogenic differentiation of human adipose-derived mesenchymal stem cells (19). A recent study has also demonstrated that cordycepin could prevent oxidative stress-induced inhibition of osteogenesis (20).…”

Tumor necrosis factor‐alpha inhibits osteogenic differentiation of pre‐osteoblasts by downregulation of EphB4 signaling via activated nuclear factor‐kappaB signaling pathway

“…9,10 The direct inhibitory effect of TNFα on osteogenic differentiation in vitro was first proposed by Canalis in 1987. 11 Further studies including our previous report have demonstrated that TNFα inhibits osteogenic differentiation of a variety of mesenchymal stem cells (MSCs), such as bone marrow-derived MSCs, [12][13][14] human dental pulp stem cells, 15,16 human adipose-derived MSCs, 17 periodontal ligament stem cells [18][19][20] and C2C12 stem cells. 21 Moreover, an in vivo study showed that null for TNFα or its p55 receptor in mice significantly increased peak bone mass, resulting exclusively from elevated bone formation, indicating that TNFα potently suppressed bone formation.…”

“…22 Many signaling pathways, particularly nuclear factor kappaB (NF-κB) signaling, have been widely investigated in TNFα-induced osteogenesis inhibition. 13,14,17,23 Blockade of NF-κB signaling protects against TNFα-induced inhibition of osteogenic differentiation of cells, such as murine ST2 MSCs, human adipose-derived MSCs and C2C12 cells. 14,17,23 Therefore, the activation of NF-κB signaling plays a central role in TNFα-induced impairment of osteogenic differentiation.…”

The novel application of cordycepin in maintaining stem cell pluripotency and increasing iPS cell generation efficiency

“…Interestingly, it was also found to protect against cerebral ischemia injury 7 . A previous study indicated that cordycepin prevented the TNF-α-induced inhibition of osteogenic differentiation of human adipose-derived mesenchymal stem cells 8 . Nevertheless, the role of cordycepin on maintaining the pluripotency of ES and iPS cells was still unclear.…”