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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Physalin D inhibits RANKL-induced osteoclastogenesis and bone loss via regulating calcium signaling

  • Ding, Ning (Department of Blood Purification, General Hospital of Shenyang Military Area Command) ;
  • Lu, Yanzhu (Department of Orthopedics, Southwest Hospital, Third Military Medical University (Army Medical University)) ;
  • Cui, Hanmin (Department of Blood Purification, General Hospital of Shenyang Military Area Command) ;
  • Ma, Qinyu (Department of Orthopedics, Southwest Hospital, Third Military Medical University (Army Medical University)) ;
  • Qiu, Dongxia (Department of Blood Purification, General Hospital of Shenyang Military Area Command) ;
  • Wei, Xueting (Department of Blood Purification, General Hospital of Shenyang Military Area Command) ;
  • Dou, Ce (Department of Orthopedics, Southwest Hospital, Third Military Medical University (Army Medical University)) ;
  • Cao, Ning (Department of Blood Purification, General Hospital of Shenyang Military Area Command)
  • Received : 2019.05.27
  • Accepted : 2019.08.29
  • Published : 2020.03.31
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Abstract

We investigated the effects of physalin A, B, D, and F on osteoclastogenesis induced by receptor activator of nuclear factor κB ligand (RANKL). The biological functions of different physalins were first predicted using an in silico bioinformatic tool (BATMAN-TCM). Afterwards, we tested cell viability and cell apoptosis rate to analyze the cytotoxicity of different physalins. We analyzed the inhibitory effects of physalins on RANKL-induced osteoclastogenesis from mouse bone-marrow macrophages (BMMs) using a tartrate-resistant acid phosphatase (TRAP) stain. We found that physalin D has the best selectivity index (SI) among all analyzed physalins. We then confirmed the inhibitory effects of physalin D on osteoclast maturation and function by immunostaining of F-actin and a pit-formation assay. On the molecular level, physalin D attenuated RANKL-evoked intracellular calcium ([Ca(2+)](i)) oscillation by inhibiting phosphorylation of phospholipase Cγ2 (PLCγ2) and thus blocked the downstream activation of Ca2+/calmodulin-dependent protein kinases (CaMK)IV and cAMP-responsive element-binding protein (CREB). An animal study showed that physalin D treatment rescues bone microarchitecture, prevents bone loss, and restores bone strength in a model of rapid bone loss induced by soluble RANKL. Taken together, these results suggest that physalin D inhibits RANKL-induced osteoclastogenesis and bone loss via suppressing the PLCγ2-CaMK-CREB pathway.

Keywords

References

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