CFTR mediates Cl- transport in osteocytes to sustain cell viability and skeletal homeostasis

  • Nat Commun. 2026 Apr 28;17(1):5796. doi: 10.1038/s41467-026-72349-0.
Peijie Hu  #  1 ,  Wanting Du  #  1 ,  Muyan Chu  #  1 ,  Junjiang Chen  1 ,  Xiaotian Zhang  1 ,  Ziyi Chen  1  2  3 ,  Jun Hu  4 ,  Lei Qin  5 ,  Wayne Yuk-Wai Lee  2 ,  Jinghui Guo  6 ,  Hui Chen  1 ,  Ruiyao Xu  1 ,  Xiaojun Cai  1 ,  Xiaohua Jiang  3 ,  Hsiao Chang Chan  3 ,  Ling Qin  7 ,  Jiankun Xu  8 ,  Ye Chun Ruan  9  10  11
Affiliations
  • 1. Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong, China.
  • 2. Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China.
  • 3. Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
  • 4. First Affiliated Hospital, Shantou University Medical College, Shantou, China.
  • 5. Department of Orthopaedics, Shenzhen Nanshan People's Hospital, the Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, China.
  • 6. School of Medicine, The Chinese University of Hong Kong, Shenzhen, China.
  • 7. Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China. [email protected].
  • 8. Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China. [email protected].
  • 9. Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong, China. [email protected].
  • 10. Research Institute for Smart Ageing, The Hong Kong Polytechnic University, Hong Kong, China. [email protected].
  • 11. Joint Research Center for Biosensing and Precision Theranostics, The Hong Kong Polytechnic University, Hong Kong, China. [email protected].
  • # Contributed equally.
PMID: 42045243 DOI: 10.1038/s41467-026-72349-0
Abstract

Osteocytes are long-lived with underlying mechanisms largely unknown. Here, we report that osteocyte-specific knockout of cystic fibrosis transmembrane conductance regulator (CFTR) results in excessive osteocyte death, proinflammatory cytokine surge, osteoclast overactivation and bone formation impairment leading to bone loss in adult mice. Consistently in MLO‑Y4 osteocyte‑line, CFTR-knockout causes progressive cell death, which is reversed by CFTR overexpression or medium replenishment. A massive proinflammatory osteocyte secretome is evoked by CFTR-knockout, which deteriorates wild-type osteocytes, inhibits osteogenic differentiation, while robustly stimulates osteoclastogenic differentiation in vitro. Patch-clamp/Cl--imaging verifies CFTR to mediate Cl- transport in osteocytes, while Cl--deprivation mimics CFTR-knockout to trigger transcriptomic/proteomic changes, cell stress and death. Additionally, osteocyte CFTR is downregulated in aged human bones; local delivery of CFTR via adenovirus or a CFTR modulator increases viable osteocytes and bone mass in aged mice. Together, the present study reveals a direct role of CFTR-mediated Cl- transport in sustaining osteocyte viability and skeletal homeostasis.

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