Ataluren prevented bone loss induced by ovariectomy and aging in mice through the BMP-SMAD signaling pathway

Lijun Zeng; Ranli Gu; Wei Li; Yuzi Shao; Yuan Zhu; Zhengwei Xie; Hao Liu; Yongsheng Zhou

doi:10.1016/j.biopha.2023.115332

Ataluren prevented bone loss induced by ovariectomy and aging in mice through the BMP-SMAD signaling pathway

Biomed Pharmacother. 2023 Oct:166:115332. doi: 10.1016/j.biopha.2023.115332. Epub 2023 Aug 17.

Authors

Lijun Zeng¹, Ranli Gu¹, Wei Li², Yuzi Shao¹, Yuan Zhu¹, Zhengwei Xie³, Hao Liu⁴, Yongsheng Zhou⁵

Affiliations

¹ Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing 100081, China; National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & National Health Commission Key Laboratory of Digital Technology of Stomatology, Beijing 100081, China.
² Department of Oral Pathology, Peking University School and Hospital of Stomatology, Beijing 100081, China; National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & National Health Commission Key Laboratory of Digital Technology of Stomatology, Beijing 100081, China.
³ Peking University International Cancer Institute, Peking University Health Science Center, Peking University, 38 Xueyuan Lu, Haidian District, Beijing 100191, China. Electronic address: xiezhengwei@hsc.pku.edu.cn.
⁴ Central Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, China; National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & National Health Commission Key Laboratory of Digital Technology of Stomatology, Beijing 100081, China. Electronic address: kqliuhao@bjmu.edu.cn.
⁵ Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing 100081, China; National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & National Health Commission Key Laboratory of Digital Technology of Stomatology, Beijing 100081, China. Electronic address: kqzhouysh@hsc.pku.edu.cn.

PMID: 37597324
DOI: 10.1016/j.biopha.2023.115332

Abstract

Both estrogen deficiency and aging may lead to osteoporosis. Developing novel drugs for treating osteoporosis is a popular research direction. We screened several potential therapeutic agents through a new deep learning-based efficacy prediction system (DLEPS) using transcriptional profiles for osteoporosis. DLEPS screening led to a potential novel drug examinee, ataluren, for treating osteoporosis. Ataluren significantly reversed bone loss in ovariectomized mice. Next, ataluren significantly increased human bone marrow-derived mesenchymal stem cell (hBMMSC) osteogenic differentiation without cytotoxicity, indicated by the high expression index of osteogenic differentiation genes (OCN , BGLAP, ALP, COL1A, BMP2, RUNX2). Mechanistically, ataluren exerted its function through the BMP-SMAD pathway. Furthermore, it activated SMAD phosphorylation but osteogenic differentiation was attenuated by BMP2-SMAD inhibitors or small interfering RNA of BMP2. Finally, ataluren significantly reversed bone loss in aged mice. In summary, our findings suggest that the DLEPS-screened ataluren may be a therapeutic agent against osteoporosis by aiding hBMMSC osteogenic differentiation.

Keywords: Ataluren; BMP-SMAD pathway; HBMMSC; Osteogenesis; Osteoporosis.

MeSH terms

Aging
Animals
Bone Diseases, Metabolic*
Female
Humans
Mice
Osteogenesis
Osteoporosis* / prevention & control
Ovariectomy

Substances

ataluren