2. Academic Validation
  3. Pregnane X receptor protects against age-related bone loss in males via PI3K/Akt-mediated inhibition of apoptosis

Pregnane X receptor protects against age-related bone loss in males via PI3K/Akt-mediated inhibition of apoptosis

  • Cell Death Discov. 2025 Nov 7;11(1):511. doi: 10.1038/s41420-025-02797-y.
Shangzhi Li 1 2 3,  Yu Xu 1 2 3 4,  Wenpeng Xu 3,  Dingxin Zhang 3,  Xiangyu Lin 3,  Peijie Hu 5 6,  Haipeng Si 7 8 9
Affiliations

Affiliations

  • 1 Department of Orthopedics, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China.
  • 2 Key Laboratory of Qingdao in Medicine and Engineering, Department of Orthopedics, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China.
  • 3 Department of Orthopedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 4 University of Health and Rehabilitation Sciences, Qingdao, China.
  • 5 Department of Orthopedics, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China. [email protected].
  • 6 Department of Medical Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China. [email protected].
  • 7 Department of Orthopedics, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China. [email protected].
  • 8 Key Laboratory of Qingdao in Medicine and Engineering, Department of Orthopedics, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China. [email protected].
  • 9 Department of Orthopedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. [email protected].
PMID: 41203627 DOI: 10.1038/s41420-025-02797-y
Abstract

The pregnane X receptor (Pxr) regulates metabolism and inflammation, but its roles in bone homeostasis remain elusive. This study demonstrates that Pxr deficiency in bones induces osteoporotic phenotypes, with reduced trabecular bone mass, impaired osteogenesis, increased inflammation, and Apoptosis. RNA Sequencing reveals downregulation of the PI3K/Akt signaling pathway in Pxr-deficient bones, a key pathway linked to cell survival and differentiation. In vitro, primary bone marrow mesenchymal stem cells (BMSCs) with Pxr deficiency exhibited inhibited antioxidant enzyme activity, elevated intracellular Reactive Oxygen Species level, activated pro-inflammatory cytokines, suppressed PI3K/Akt pathway, enhanced Apoptosis, and decreased osteogenic differentiation. Conversely, Pxr overexpression in BMSCs from aged mice restores PI3K/Akt activation, mitigates Apoptosis, and rescues osteogenic differentiation, with these multidirectional beneficial effects abrogated by a PI3K/Akt Inhibitor. Moreover, both genetical overexpression of Pxr and pharmacological activation of Pxr improve bone quality in aged mice. These findings identify Pxr as a key regulator of bone homeostasis via the PI3K/Akt pathway, suggesting Pxr as a potential treatment target for age-related bone loss.

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