TY - JOUR
T1 - Targeted inhibition of osteoclastogenesis reveals the pathogenesis and therapeutics of bone loss under sympathetic neurostress
AU - Sui, Bingdong
AU - Liu, Jin
AU - Zheng, Chenxi
AU - Dang, Lei
AU - Chen, Ji
AU - Cao, Yuan
AU - Zhang, Kaichao
AU - Liu, Lu
AU - Dang, Minyan
AU - Zhang, Liqiang
AU - Chen, Nan
AU - He, Tao
AU - Xuan, Kun
AU - Jin, Fang
AU - Zhang, Ge
AU - Jin, Yan
AU - Hu, Chenghu
N1 - Funding Information:
This work was supported by grants from the National Natural Science Foundation of China (81870796, 82170988, 81930025 and 82100969), the General Research Funds from the Research Grants Council of Hong Kong SAR (12114416, 12100918, 12136616 and 12103519) and the China Postdoctoral Science Foundation (2019M663986 and BX20190380).
Publisher Copyright:
© The Author(s) 2022
PY - 2022/8/1
Y1 - 2022/8/1
N2 - 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 β2-adrenergic receptor (β2AR) 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-Asp8)-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.
AB - 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 β2-adrenergic receptor (β2AR) 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-Asp8)-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.
UR - http://www.scopus.com/inward/record.url?scp=85135153108&partnerID=8YFLogxK
U2 - 10.1038/s41368-022-00193-1
DO - 10.1038/s41368-022-00193-1
M3 - Journal article
SN - 1674-2818
VL - 14
JO - International journal of oral science
JF - International journal of oral science
M1 - 39
ER -
