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BMP-6 exerts its osteoinductive effect through activation of IGF-I and EGF pathways

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Abstract

We have recently shown that human recombinant BMP-6 (rhBMP-6), given systematically, can restore bone in animal models of osteoporosis. To further elucidate the underlying mechanisms of new bone formation following systemic application of BMPs, we conducted gene expression profiling experiments using bone samples of oophrectomised mice treated with BMP-6. Gene set enrichment analysis revealed enrichment of insulin-like growth factor-I and epidermal growth factor related pathways in animals treated with BMP-6. Significant upregulation of IGF-I and EGF expression in bones of BMP-6 treated mice was confirmed by quantitative PCR. To develop an in vitro model for evaluation of the effects of BMP-6 on cells of human origin, we cultured primary human osteoblasts. Treatment with rhBMP-6 accelerated cell differentiation as indicated by the formation of mineralised nodules by day 18 of culture versus 28–30 days in vehicle treated cultures. In addition, alkaline phosphatase gene expression and activity were dramatically increased upon BMP-6 treatment. Expression of IGF-I and EGF was upregulated in human osteoblast cells treated with BMP-6. These results collectively indicate that BMP-6 exerts its osteoinductive effect, at least in part, through IGF-I and EGF pathways, which can be observed both in a murine model of osteopenia and in human osteoblasts.

Résumé

Nous avons récemment pu mettre en évidence que la BMP-6 (rhBMP-6), administrée de façon systématique, pouvait améliorer la restauration du capital osseux de modèles animaux avec ostéoporose. Nous avons conduit une expérimentation utilisant des souris ovarieactomisées traitées par BMP-6. L’analyse a montré qu’il y avait un apport d’insulin like growth factor et d’épidermal growth factor chez les animaux traités par BMP-6. Pour développer un modèle in vitro nous avons étudié l’effet de la BMP-6 sur les cellules de type ostéoplasties d’origine humaine. Le traitement par BMP-6 accélère la différenciation cellulaire au 18ème jour alors que normalement cette différence est notée aux alentours du 28ème et 30ème jour. De plus, l’expression du gène de la phosphatase alkaline et l’activité sont augmentées par le traitement par la BMP-6, de même en ce qui concerne l’IGF-1 et l’EGF. Ces résultats nous permettent de penser que le BMP-6 a un effet ostéo conducteur notamment pour les pathologies intéressant IGF-1 et EGF. Nous avons observé ces effets dans un modèle animal avec ostéoplastie et sur les ostéoblastes humains.

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Acknowledgments

The authors acknowledge the great help of Djurdjica Car and Mirjana Palcic for performing animal studies.

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Authors and Affiliations

  1. Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA

    W. A. Grasser, K. A. Riccardi & V. M. Paralkar

  2. Department of Anatomy, School of Medicine, University of Zagreb, Zagreb, Croatia

    I. Orlic, P. Simic & S. Vukicevic

  3. Center for Functional Genomics, School of Medicine, University of Zagreb, Zagreb, Croatia

    F. Borovecki

  4. Laboratory of Mineralized Tissues, School of Medicine, University of Zagreb, Salata 11, 10 000, Zagreb, Croatia

    S. Vukicevic

Authors
  1. W. A. Grasser
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  2. I. Orlic
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  3. F. Borovecki
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  4. K. A. Riccardi
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  5. P. Simic
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  6. S. Vukicevic
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  7. V. M. Paralkar
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Corresponding authors

Correspondence to S. Vukicevic or V. M. Paralkar.

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W.A. Grasser and I. Orlic equally contributed to the results of this manuscript.

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Grasser, W.A., Orlic, I., Borovecki, F. et al. BMP-6 exerts its osteoinductive effect through activation of IGF-I and EGF pathways. International Orthopaedics (SICO 31, 759–765 (2007). https://doi.org/10.1007/s00264-007-0407-9

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  • DOI: https://doi.org/10.1007/s00264-007-0407-9

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