State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, China.
Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
Int J Oral Sci. 2022 Aug 1;14(1):39. doi: 10.1038/s41368-022-00193-1.
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 (βAR) 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)-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.
交感神经线索通过肾上腺素能信号对骨稳态进行严格调节，并有助于神经应激引起的骨质流失，但机制和治疗方法仍不完全清楚。在这里，我们揭示了在交感-肾上腺素能激活下，以破骨细胞为中心的功能性重要的骨质疏松发病机制，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 受到交感-肾上腺素能线索的严格调节，这些线索是由β2-肾上腺素能受体（βAR）信号的下游传递的，通过抑制程序性细胞死亡因子 4（Pdcd4），在体内对破骨细胞生成进行了关键调节，并介导了异丙肾上腺素（ISO）和慢性可变应激（CVS）对骨骼的有害影响。有趣的是，通过（D-Asp）-脂质纳米颗粒介导的靶向抑制破骨细胞 miR-21 或通过临床相关药物抑制破骨细胞生成，在不影响成骨细胞骨形成的情况下，足以实现对 ISO 和 CVS 的骨保护。总的来说，这些结果揭示了一个以前未被充分确定的分子和功能范例，即破骨细胞生成对骨的交感-肾上腺素能调节至关重要，并建立了多种靶向治疗策略，以对抗应激下的骨质疏松症。
