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Physalin D Inhibits RANKL-induced Osteoclastogenesis and Bone Loss via Modulating Calcium Signaling
Ning Ding1,#, Yanzhu Lu2,#, Hanmin Cui1, Qinyu Ma2, Dongxia Qiu1, Xueting Wei1, Ce Dou2,*, Ning Cao1,*
1Department of Blood Purification, General Hospital of Shenyang Military Area Command,
2Department of Orthopaedics, Third Military Medical University
Abstract
The effects of physalin A, B, D and F on receptor activator of nuclear factor リB ligand (RANKL) induced osteoclastogenesis were investigated. The biological functions of different physalins were first predicted using an in silico bioinformatic tool (BATMAN-TCM). Afterwards, cell viability and cell apoptosis rate were tested for analyzing the cytotoxicity of different physalins. The inhibitory effects of physalins on RANKL induced osteoclastogenesis from mouse bone marrow macrophages (BMMs) were analyzed using tartrate resistant acid phosphatase (TRAP) stain. The results revealed that physalin D has the best selectivity index (SI) among all analyzed physalins. The inhibitory effects of physalin D on osteoclast maturation and function were then confirmed by immunostaining of F-actin and pit formation assay. On the molecular level, physalin D attenuated RANKL evoked intracellular calcium ([Ca(2+)](i)) oscillation by inhibiting phosphorylation of phospholipase Cャ2 (PLCャ2) thus blocked the downstream activation of Ca2+/calmodulin-dependent protein kinases (CaMK)IV and cAMP-responsive element binding protein (CREB). Animal study showed that physalin D treatment rescues bone microarchitecture, prevents bone loss, and restores bone strength in a rapid bone loss model induced by soluble RANKL. Taken together, these results suggest that physalin D inhibits RANKL-induced osteoclastogenesis and bone loss via suppressing PLCャ2-CaMK-CREB pathway.
Abstract, Accepted Manuscript(in press) [Submitted on May 27, 2019, Accepted on August 29, 2019]
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