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Targeting FoxO transcription factors with HDAC inhibitors for the treatment of osteoarthritis
  1. Hiroki Ohzono1,2,
  2. Yiwen Hu1,3,
  3. Keita Nagira1,4,
  4. Haruhisa Kanaya1,4,
  5. Naoki Okubo1,5,
  6. Merissa Olmer6,
  7. Masafumi Gotoh2,
  8. Ichiro Kurakazu6,7,
  9. Yukio Akasaki8,
  10. Manabu Kawata1,
  11. Emily Chen9,
  12. Alan C Chu9,
  13. Kristen A Johnson9,
  14. Martin K Lotz1
  1. 1 Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA
  2. 2 Department of Orthopaedic Surgery, Kurume University Hospital, Kurume, Japan
  3. 3 Department of Radiology, Fudan University, Shanghai, China
  4. 4 Department of Orthopaedic Surgery, Tottori University, Tottori, Japan
  5. 5 Department of Orthopaedics, Kyoto Prefectural University of Medicine, Kyoto, Japan
  6. 6 The Scripps Research Institute, La Jolla, California, USA
  7. 7 Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Kyushu, Japan
  8. 8 Department of Orthopaedics, Kyushu University, Kyushu, UK
  9. 9 Calibr, a Division of Scripps Research Institute, La Jolla, California, USA
  1. Correspondence to Professor Martin K Lotz, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037, USA; mlotz{at}


Objectives Osteoarthritis (OA) features ageing-related defects in cellular homeostasis mechanisms in articular cartilage. These defects are associated with suppression of forkhead box O (FoxO) transcription factors. FoxO1 or FoxO3 deficient mice show early onset OA while FoxO1 protects against oxidative stress in chondrocytes and promotes expression of autophagy genes and the essential joint lubricant proteoglycan 4 (PRG4). The objective of this study was to identify small molecules that can increase FoxO1 expression.

Methods We constructed a reporter cell line with FoxO1 promoter sequences and performed high-throughput screening (HTS) of the Repurposing, Focused Rescue and Accelerated Medchem (ReFRAME) library . Hits from the HTS were validated and function was assessed in human chondrocytes, meniscus cells and synoviocytes and following administration to mice. The most promising hit, the histone deacetylase inhibitor (HDACI) panobinostat was tested in a murine OA model.

Results Among the top hits were HDACI and testing in human chondrocytes, meniscus cells and synoviocytes showed that panobinostat was the most promising compound as it increased the expression of autophagy genes and PRG4 while suppressing the basal and IL-1β induced expression of inflammatory mediators and extracellular matrix degrading enzymes. Intraperitoneal administration of panobinostat also suppressed the expression of mediators of OA pathogenesis induced by intra-articular injection of IL-1β. In a murine OA model, panobinostat reduced the severity of histological changes in cartilage, synovium and subchondral bone and improved pain behaviours.

Conclusion Panobinostat has a clinically relevant activity profile and is a candidate for OA symptom and structure modification.

  • Osteoarthritis
  • Chondrocytes
  • Inflammation

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.

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Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.

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  • Handling editor Josef S Smolen

  • Collaborators Hiroki Ohzono, Yiwen Hu, Keita Nagira, Haruhisa Kanaya, Naoki Okubo, Merissa Olmer, Masafumi Gotoh, Ichiro Kurakazu, Yukio Akasaki, Manabu Kawata, Emily Chen, Alan C. Chu, Kristen A. Johnson, Martin K. Lotz.

  • Contributors MKL initiated project. MKL, YK and MG were responsible for study design. KN and NO developed the reporter cell lines. KAJ supervised the drug screening. EC and ACC performed the drug screening. HO and HK conducted in vitro studies and performed the mouse model studies. HO, MK, IK and MO performed pain testing and histological analyses. MKL and HO wrote the manuscript. YH performed mechanistic studies. All authors approved the final manuscript. MKL acts as guarantor.

  • Funding National Institutes of Health grants AG049617 and AG059418.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.