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 o...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 micro RNA response and efficient therapeutics.We discovered that osteoclastic mi R-21 was tightly regulated by sympatho-adrenergic cues downstream theβ2-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 mi R-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.展开更多
基金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)the China Postdoctoral Science Foundation(2019M663986 and BX20190380)。
文摘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 micro RNA response and efficient therapeutics.We discovered that osteoclastic mi R-21 was tightly regulated by sympatho-adrenergic cues downstream theβ2-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 mi R-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.
