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.

通过肾上腺素能信号传导的交感神经信号可严格调节骨稳态并导致神经应激诱导的骨丢失，但其机制和治疗方法仍未完全阐明。在这里，我们揭示了交感神经 - 肾上腺素能激活下以破骨细胞生成为中心的功能重要的骨质减少发病机制，具有特征性的 microRNA 反应和有效的治疗方法。我们发现破骨细胞 miR-21 受 β2-肾上腺素能受体 ( _β2AR) 信号，通过抑制程序性细胞死亡 4 (Pdcd4) 在体内严格调节破骨细胞生成，并介导异丙肾上腺素 (ISO) 和慢性可变应力 (CVS) 对骨骼的有害影响。有趣的是，在不影响成骨细胞骨形成的情况下，通过 (D-Asp ₈ )-脂质纳米颗粒介导的破骨细胞 miR-21 靶向抑制或通过临床相关药物抑制破骨细胞生成，可以充分实现对 ISO 和 CVS 的骨保护。总的来说，这些结果揭示了以前未确定的分子和功能范式，即破骨细胞生成对骨的交感神经 - 肾上腺素能调节至关重要，并建立了多种靶向治疗策略来对抗压力下的骨质减少。