期刊
INTERNATIONAL JOURNAL OF ORAL SCIENCE
卷 14, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41368-022-00193-1
关键词
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资金
- National Natural Science Foundation of China [81870796, 82170988, 81930025, 82100969]
- General Research Funds from the Research Grants Council of Hong Kong SAR [12114416, 12100918, 12136616, 12103519]
- China Postdoctoral Science Foundation [2019M663986, BX20190380]
This study reveals the crucial role of sympathetic cues in regulating bone homeostasis and neurostress-induced bone loss. The research focuses on the impact of sympatho-adrenergic activation on osteoclastogenesis and identifies miR-21 as a key regulator in this process. Targeted inhibition of miR-21 or suppression of osteoclastogenesis using drugs can protect bone against stress-induced osteopenias.
Sympathetic cues via the adrenergic signaling critically regulate bone homeostasis and contribute to neurostress-induced bone loss, but the mechanisms and therapeutics remain incompletely elucidated. Here, we reveal an osteoclastogenesis-centered functionally important osteopenic pathogenesis under sympatho-adrenergic activation with characterized microRNA response and efficient therapeutics. We discovered that osteoclastic miR-21 was tightly regulated by sympatho-adrenergic cues downstream the beta 2-adrenergic receptor (beta(2)AR) signaling, critically modulated osteoclastogenesis in vivo by inhibiting programmed cell death 4 (Pdcd4), and mediated detrimental effects of both isoproterenol (ISO) and chronic variable stress (CVS) on bone. Intriguingly, without affecting osteoblastic bone formation, bone protection against ISO and CVS was sufficiently achieved by a (D-Asp(8))-lipid nanoparticle-mediated targeted inhibition of osteoclastic miR-21 or by clinically relevant drugs to suppress osteoclastogenesis. Collectively, these results unravel a previously underdetermined molecular and functional paradigm that osteoclastogenesis crucially contributes to sympatho-adrenergic regulation of bone and establish multiple targeted therapeutic strategies to counteract osteopenias under stresses.
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