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  3. Targeted inhibition of osteoclastogenesis reveals the pathogenesis and therapeutics of bone loss under sympathetic neurostress

Targeted inhibition of osteoclastogenesis reveals the pathogenesis and therapeutics of bone loss under sympathetic neurostress

  • Int J Oral Sci. 2022 Aug 1;14(1):39. doi: 10.1038/s41368-022-00193-1.
Bingdong Sui  # 1,  Jin Liu  # 2 3,  Chenxi Zheng 1,  Lei Dang 2,  Ji Chen 1,  Yuan Cao 1,  Kaichao Zhang 1 4,  Lu Liu 1,  Minyan Dang 1 4,  Liqiang Zhang 1 4,  Nan Chen 1,  Tao He 1,  Kun Xuan 1,  Fang Jin 1,  Ge Zhang 2,  Yan Jin 5 6,  Chenghu Hu 7 8 9 10
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China.
  • 4 Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, China.
  • 5 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. yanjin@fmmu.edu.cn.
  • 6 Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, China. yanjin@fmmu.edu.cn.
  • 7 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. chenghu@xiterm.com.
  • 8 Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China. chenghu@xiterm.com.
  • 9 Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, China. chenghu@xiterm.com.
  • 10 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China. chenghu@xiterm.com.
  • # Contributed equally.
PMID: 35915088 DOI: 10.1038/s41368-022-00193-1
Abstract

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.

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