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Decreased levels of nucleotide pyrophosphatase phosphodiesterase 1 are associated with cartilage calcification in osteoarthritis and trigger osteoarthritic changes in mice
  1. J Bertrand1,
  2. Y Nitschke2,
  3. M Fuerst3,
  4. S Hermann4,
  5. M Schäfers4,5,
  6. J Sherwood1,
  7. G Nalesso1,
  8. W Ruether6,
  9. F Rutsch2,
  10. F Dell'Accio1,
  11. T Pap7
  1. 1Department of Experimental Medicine and Rheumatology, Barts and The London, Queen Mary School of Medicine and Dentistry, William Harvey Research Institute, London, UK
  2. 2Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany
  3. 3Department for Orthopedics and Trauma Surgery, MedBaltic, Neumünster, Germany
  4. 4European Institute for Molecular Imaging, University of Münster, Germany
  5. 5Department of Nuclear Medicine, University Hospital Münster, Münster, Germany
  6. 6Centre for Orthopaedics and Trauma Surgery Bad Bramstedt, University hospital Hamburg-Eppendorf, Germany
  7. 7Institute for Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
  1. Correspondence to Jessica Bertrand, Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Domagkstraße 3, D-48149 Münster, Germany; bertrand{at}uni-muenster.de

Abstract

Objective To analyse the function of nucleotide pyrophosphatase phosphodiesterase (NPP1), a member of the pyrophosphate pathway, in osteoarthritis (OA).

Methods mRNA expression of NPP1, ANK ankylosing protein and tissue non-specific alkaline phosphatase was assessed by quantitative PCR. NPP1 protein levels were analysed in mouse and human cartilage samples. Bone metabolism was analysed by F18-positron emission tomography-scanning and µCT in ttw/ttw mice. Ttw/ttw mice are mice carrying a loss-of-function mutation in NPP1. Calcification of articular cartilage was assessed using von Kossa staining and OA severity using the Mankin score. Cartilage remodelling was investigated by type X collagen immunohistochemistry.

Results Expression of NPP1, but not the other members of this pathway, inversely correlated with cartilage calcification and OA severity in mouse and humans. Proinflammatory cytokines downregulated the expression of NPP1, demonstrating an influence of inflammation on matrix calcification. Ttw/ttw mutant mice, carrying a loss-of-function mutation in NPP1, exhibit increased bone formation process in joints compared with wild types. Ttw/ttw mice also developed spontaneous OA-like changes, evaluated by histological analysis and in vivo imaging. Ectopic calcifications were associated with increased expression of collagen X in the cartilage.

Conclusion The authors conclude that OA is characterised by the reactivation of molecular signalling cascades involving proinflammatory cytokines, thereby regulating the pyrophosphate pathway which consequently leads to cartilage ossification, at least in part resembling endochondral ossification.

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Footnotes

  • JB and YN are joint first authors and FD and TP are joint last authors.

  • Funding This work was supported by the Interdisciplinary Centre of Clinical Research (IZKF core unit SmAP), Münster Germany and funded by the DFG (Pa689/12).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by the ethics committee of the Ärztekammer Schleswig- Holstein, Bad Segeberg, Germany.

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

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