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A4.9 How Osteoblast Regulates Energy Metabolism and Systemic Inflammation Dependent of FRA-2 Expression
  1. Aline Bozec1,
  2. Yubin Luo1,
  3. Christine Zech1,
  4. Maria Jimenez2,
  5. Latifa Bakiri2,
  6. Mirco Petrucelli2,
  7. Michael Amling3,
  8. Georg Schett1,
  9. Erwin Wagner2
  1. 1Department of Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, Nikolaus-Fiebiger-ZentrumGlueckstrasse 6, D-91054 Erlangen, Germany
  2. 2Genes, Development and Disease Group, F-BBVA-CNIO Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid
  3. 3Department of Osteology and Biomechanics, University Medical Center, Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany

Abstract

Background and Objectives The transcription factor Fra-2 (Fosl2) is a member of the AP-1 complex and an important regulator of bone homeostasis. We have previously shown that Fra-2 controls bone development, osteoclast size [1] and osteoblast differentiation through direct regulation of Collagen 1a2 and Osteocalcin (Ocn) [2]. Recent studies have established that the skeleton functions as an endocrine organ affecting metabolism through Ocn [3], although only few transcription factors and only one osteoblast-derived hormone are known to affect the crosstalk between bone and metabolism.

Materials and Methods We have generated mice with specific deletion of Fra-2 (Fosl2) or ectopic expression of Fra-2 in osteoblast to study the role of Fra-2 beyond the bone e.g. in metabolism.

Results Here we show that mice with osteoblast specific deletion of Fra-2 (Fosl2) have despite a low bone mass, an increased body weight. In contrast, ectopic expression of Fra-2 in osteoblasts display increased bone mass and decreased body weight accompanied with reduced serum glucose and insulin levels, improved glucose tolerance and insulin sensitivity. In addition, these Fra-2 mutant mice are protected from metabolic impairment, when challenged with high fat diet (HFD). Surprisingly a systemic inflammation and macrophage infiltration in liver, spleen and lung was observed in Fra-2 osteoblast specific mice. Mechanistically, we showed that in osteoblasts Fra-2 transcriptionally represses an important adipo-cytokine Adiponectin (Adipoq), while it induces Ocn, both responsible for the glucose and insulin metabolism alteration. Whereas, the systemic inflammation was likely due to the transcriptional increased of Osteopontin (OPN) expression by Fra-2, which is known as a potent inductor of macrophage activation.

Conclusions Taking together these results show that Fra-2 expression in osteoblast transcriptionally modulates Adipoq, Ocn and OPN expression and secretion representing a novel mechanism for the endocrine function of the skeleton on systemic metabolism and inflammation.

References

  1. Bozec A, et al, (2008). Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia. Nature 454(7201):221–225.

  2. Bozec A, et al, (2010). Fra-2/AP-1 controls bone formation by regulating osteoblast differentiation and collagen production. The Journal of cell biology 190(6):1093–1106.

  3. Karsenty G & Ferron M (2012). The contribution of bone to whole-organism physiology. Nature 481(7381):314–320.

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