2. Academic Validation
  3. A multi-model approach identifies ALW-II-41-27 as a promising therapy for osteoarthritis-associated inflammation and endochondral ossification

A multi-model approach identifies ALW-II-41-27 as a promising therapy for osteoarthritis-associated inflammation and endochondral ossification

  • Heliyon. 2024 Dec 4;10(23):e40871. doi: 10.1016/j.heliyon.2024.e40871.
Mauricio N Ferrao Blanco 1,  Raphaelle Lesage 2 3,  Nicole Kops 1,  Niamh Fahy 1 4 5,  Fjodor T Bekedam 1,  Athina Chavli 1,  Yvonne M Bastiaansen-Jenniskens 1,  Liesbet Geris 2 3 6,  Mark G Chambers 7,  Andrew A Pitsillides 8,  Roberto Narcisi 1,  Gerjo J V M van Osch 1 9 10
Affiliations

Affiliations

  • 1 Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
  • 2 Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Belgium.
  • 3 Biomechanics Section, KU Leuven, Belgium.
  • 4 Department of Oral and Maxillofacial Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
  • 5 Department of Applied Science, Technological University of the Shannon: Midlands Midwest, Limerick, Ireland.
  • 6 GIGA In Silico Medicine, University of Liège, Belgium.
  • 7 Lilly Research Laboratories, Eli Lilly Pharmaceuticals, Indianapolis, USA.
  • 8 Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom.
  • 9 Department of Otorhinolaryngology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
  • 10 Department of Biomechanical Engineering, University of Technology Delft, Delft, the Netherlands.
PMID: 39717596 DOI: 10.1016/j.heliyon.2024.e40871
Abstract

Low-grade inflammation and pathological endochondral ossification are key processes underlying the progression of osteoarthritis, the most prevalent joint disease worldwide. In this study, we employed a multi-faceted approach, integrating publicly available datasets, in silico analyses, in vitro experiments and in vivo models to identify new therapeutic candidates targeting these processes. Data mining of transcriptomic datasets identified EphA2, a receptor tyrosine kinase associated with Cancer, as being linked to both inflammation and endochondral ossification in osteoarthritis. A computational model of cellular signaling networks in chondrocytes predicted that in silico activation of EphA2 in healthy chondrocytes increases inflammatory mediators and induces hypertrophic differentiation, a hallmark of endochondral ossification. We then evaluated the effect of EphA2 inhibition using the tyrosine kinase inhibitor ALW-II-41-27 in cultured human chondrocytes from individuals with osteoarthritis, demonstrating significant reductions in both inflammation and hypertrophy. Additionally, systemic subcutaneous administration of ALW-II-41-27 in a mouse osteoarthritic model attenuated joint degeneration by reducing local inflammation and pathological endochondral ossification. Collectively, this study demonstrates a novel drug discovery pipeline that integrates computational, experimental, and animal models, paving the way for the development of disease-modifying treatments for osteoarthritis.

Keywords

Author e-mails; Chondrocyte hypertrophy; Drug target; Inflammation; Kinase inhibitor; Virtual cell.

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