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INTERBONE - the interplay among bone cells, matrices and systems

Project objectives

The skeleton does more than provide just a physical structure to the body. Bone cells play an important role in metabolism, in regulating health and protecting against disease. There is a highly complex web of interactions between bone cells, the other components of skeletal tissue, and cells and organs in other parts of the body. This is still poorly understood.

INTERBONE, an interdisciplinary network for international exchange of scientists, was supported by the European Union Framework 7 programme to study the central role of the skeleton in three areas of health. Work on energy metabolism in INTERBONE built on previous research findings that suggest a link between bone-derived signals, glucose metabolism and insulin sensitivity. The network also investigated the role of candidate secreted factors in the disruption of hematopoiesis in the development of leukemia. Research on fracture repair and tissue regeneration has addressed biomaterials interactions with cells, and stimulation of angiogenesis in fracture repair with biophysical approaches.

The network, coordinated by Professor Anna Maria Teti at the University of L’Aquila, Italy, aimed to integrate research and training activities between 6 institutions:

  • University of L’Aquila, Italy
  • Erasmus Medical Centre, Netherlands
  • Universidade do Grande Rio, Brazil
  • Universidade Estadual Paulista, Brazil
  • Anna University, Chennai, India
  • Columbia University, USA

The planned research collaboration was supported by a programme of staff exchanges, training and networking activities. The network planned regular meetings integrated with established international conferences in bone-related research, to support networking and dissemination, a workshop on tissue regeneration and angiogenesis, and a programme of webinars. INTERBONE aimed to make a contribution to the opening of the European Research Area to international cooperation, and interaction with three of Europe’s strategic global partners (USA, India and Brazil) in this emerging interdisciplinary area of research.

Progress and results

INTERBONE exchanges involved 21 fellows from the participating laboratories, including PhD students, experienced researchers and technicians. Fellows were trained on i) generation of animal models (conditional knock-out and transgenics), ii) in vitro and in vivo assays to determine energy metabolism, iii) endothelial cell biology and cross-talk with bone cells and hematopoietic cells, iv) bone-cell endothelial cells cross-talk in unloading conditions and tissue repair and v) use of innovative biomaterials to improve osteointegration and fracture healing. A network has been created among the fellows, with a continuous and fertilizing exchange of methods, protocols, hypothesis and experimental designs..

INTERBONE has obtained new results on in vitro and in vivo studies, that give us new knowledge on the interactions of bone and other tissues. INTERBONE results have included:

  • protocols for bone-endothelial cell and endothelial - hematopoietic cell cocultures
  • characterisation of energy metabolism in new mouse models
  • identification of a role of osteoblasts in leukemogenesis
  • kinome profile map in osteoblasts exposed to new biomaterials
  • set up of experimental methods and results on the interaction between bone cells and endothelial cells under unloading conditions
  • role of osteoblast factors in hypoxia conditions
  • role of LCN2 in bone and energy metabolism
  • characterization of mesenchymal stem cells under osteogenic conditions.

Some of our publications, with INTERBONE fellows indicated in bold:

  • Gemini‐Piperni S, Milani R, Bertazzo S, Peppelenbosch M, Takamori ER, Granjeiro JM, Ferreira CV, Teti A and Zambuzzi W. Kinome profiling of osteoblasts on hydroxyapatite opens new avenues on biomaterial cell signaling. Biotechnol. Bioeng. 2014. 111: 1900-1905. PMID: 24668294 DOI: 10.1002/bit.25246
  • Kode A, Obri A, Paone R, Kousteni S, Ducy P, Karsenty G. Lrp5 regulation of bone mass and serotonin synthesis in the gut. Nat Med. 2014 Nov;20(11):1228-9. PMID: 25375916 DOI:10.1038/nm.3698
  • Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N, Khiabanian H, Lee A, Vundavalli M, Friedman R, Brum A, Park D, Galili N, Mukherjee S, Teruya-Feldstein J, Raza A, Rabadan R, Berman E, Kousteni S. Leukemogenesis Induced by an Activating β-catenin mutation in Osteoblasts. Nature 2014 Feb 13;506(7487):240-4. PMCID:PMC4116754 DOI:10.1038/nature12883
  • Rucci N, Capulli M, Piperni SG, Cappariello A, Lau P, Frings-Meuthen P, Heer M, Teti A. Lipocalin 2: a new mechanoresponding gene regulating bone homeostasis. J Bone Miner Res. 2015 Feb;30(2):357-68. PMID: 25112732 DOI:10.1002/jbmr.2341
  • Wei J, Shimazu J, Makinistoglu MP, Maurizi A, Kajimura D, Zong H, Takarada T, Lezaki T, Pessin JE, Hinoi E, Karsenty G. Glucose Uptake and Runx2 Synergize to Orchestrate Osteoblast Differentiation and Bone Formation. Cell. 2015 Jun 18;161(7):1576-1591. PMCID:PMC4475280DOI:10.1016/j.cell.2015.05.029
  • Veeriah V, Zanniti A, Paone R, Chatterjee S, Rucci N, Teti A, Capulli M. Interleukin-1β, lipocalin 2 and nitric oxide synthase 2 are mechano-responsive mediators of mouse and human endothelial cell-osteoblast crosstalk. Sci. Rep. 2016 Jul 19;6:29880. PMCID:PMC4949438 DOI:10.1038/srep29880
  • Sartoretto S, Gemini-Piperni S, da Silva RA, Calasans MD, Rucci N, Pires Dos Santos TM, Lima IBC, Rossi AM, Alves G, Granjeiro JM, Teti A, Zambuzzi WF. Apoptosis-associated speck-like protein containing a caspase-1 recruitment domain (ASC) contributes to osteoblast differentiation and osteogenesis. J Cell Physiol. 2018 Aug 31. PMID:30171612 DOI:10.1002/jcp.27226
  • Baroncelli M, Fuhler GM, van de Peppel J, Zambuzzi WF, van Leeuwen JP, van der Eerden BCJ, Peppelenbosch MP. Human mesenchymal stromal cells in adhesion to cell-derived extracellular matrix and titanium: Comparative kinome profile analysis. J Cell Physiol. 2018 Jul 30. PMCID:30058720. DOI 10.1002/jcp.27116.

Fellows have been able to reproduce the experimental protocols set up during their exchange after returning to their home laboratories and have maintained a tight interaction and collaboration with their supervisors in the host laboratories.

Training activities also included a cycle of 7 webinars delivered by the INTERBONE principal investigators, as well as public workshops held by INTERBONE at the annual Calcified Tissue Symposia in Lisbon (May 2013), Prague (May 2014) and in Rotterdam (April 2015). INTERBONE also organised the Workshop on Wound Healing and Angiogenesis, held in Chennai (India) in December 2013. Furthermore, INTERBONE organised a special issue of the Archives of Biochemistry and Biophysics entitled “Bone: a dynamic and integrating tissue”. This issue contributed to the international visibility of INTERBONE and represented an additional collaborative task for the partners, providing opportunities for INTERBONE fellows to disseminate their results and gain complementary training in an aspect of scientific publication.

 

INTERBONE fellows working in Italy

Expected impact

We expect our INTERBONE fellows will develop their scientific careers with a strong degree of independence, mobility at the global level, and experience of interdisciplinary research. INTERBONE provided them a network of interactions with other scientists which will create a solid background for future international collaborations. We have obtained results that have been published, while further manuscripts are in preparation. Our results could have a significant impact for the bone field with new knowledge characterised by a robust translational potential, which in the future can be exploited in medicine and health science.

Three of the INTERBONE partners have continued collaboration through the Horizon 2020 RUBICON network.

Contact

For more information, please contact INTERBONE coordinator Prof Anna Maria Teti.