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Inhibition of caspase-8 cascade restrains the osteoclastogenic fate of bone marrow cells

  • Signaling and Cell Physiology
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Abstract

Osteoclasts are multinucleated cells of hematopoietic origin, with a pivotal role in bone development and remodeling. Failure in osteoclast differentiation and activation leads to various bone disorders; thus, attention has focused on a search of molecules involved in osteoclast regulatory pathways. Caspase-8 appears to be an interesting candidate for further exploration, due to its potential function in bone development and homeostasis. Mouse bone marrow cells were differentiated into osteoclasts by RANKL stimulation. Increased activation of caspase-8 and its downstream executioner caspases (caspase-3 and caspase-6) was found during osteoclastogenesis. Subsequent inhibition of caspase-8, caspase-3, or caspase-6, respectively, during osteoclast differentiation showed distinct changes in the formation of TRAP-positive multinucleated cells and reduced expression of osteoclast markers including Acp5, Ctsk, Dcstamp, and Mmp9. Analysis of bone matrix resorption confirmed significantly reduced osteoclast function after caspase inhibition. The results clearly showed the role of caspases in the proper development of osteoclasts and contributed new knowledge about non-apoptotic function of caspases.

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Funding

The research was supported the Czech Science Foundation, project GACR 21-21409S.

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Authors and Affiliations

  1. Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic

    Barbora Veselá, Adéla Ševčíková, Kateřina Holomková, Adéla Kratochvílova, Paul T. Sharpe & Eva Matalová

  2. Department of Physiology, University of Veterinary Sciences Brno, Brno, Czech Republic

    Barbora Veselá & Eva Matalová

  3. Department of Biological Sciences and Pathobiology, Centre of Biological Sciences, University of Veterinary Medicine Vienna, Vienna, Austria

    Alice Ramešová

  4. Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK

    Paul T. Sharpe

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Contributions

E.M. designed the study. B.V. planned the experiments. B.V., A.S., A.R., A.K. and K.H. performed the experiments. A.K. and P.S. analyzed the data. A.S. and B.V. prepared figures. B.V. and E.M. wrote the manuscript. All authors reviewed the manuscript.

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Correspondence to Barbora Veselá.

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The samples were obtained in agreement with the recent legislation in the Czech Republic, law 359/2012 Sb., in which there is no specific requirement for post-mortem sampling.

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Veselá, B., Ševčíková, A., Holomková, K. et al. Inhibition of caspase-8 cascade restrains the osteoclastogenic fate of bone marrow cells. Pflugers Arch - Eur J Physiol (2024). https://doi.org/10.1007/s00424-024-02977-2

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