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Adipose-tissue derived signals control bone remodelling

Maria-Bernadette Madel, He Fu, Dominique D. Pierroz, Mariano Schiffrin, Carine Winkler, Anne Wilson, Cécile Pochon, Barbara Toffoli, Jean-Yves Jouzeau, Federica Gilardi, Serge Ferrari, Nicolas Bonnet, Claudine Blin-Wakkach, Béatrice Desvergne, David Moulin
doi: https://doi.org/10.1101/2020.03.02.972711
Maria-Bernadette Madel
1CNRS UMR7370, Laboratoire de PhysioMédecine Moléculaire, Nice, France
2Université Côte d'Azur, Nice, France
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He Fu
3Center for Integrative Genomics, Genopode, Lausanne Faculty of Biology and Medicine CH-1015 Lausanne, Switzerland
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Dominique D. Pierroz
4International Osteoporosis Foundation, 1260 Nyon, Switzerland
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Mariano Schiffrin
3Center for Integrative Genomics, Genopode, Lausanne Faculty of Biology and Medicine CH-1015 Lausanne, Switzerland
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Carine Winkler
3Center for Integrative Genomics, Genopode, Lausanne Faculty of Biology and Medicine CH-1015 Lausanne, Switzerland
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Anne Wilson
5Ludwig Centre for Cancer Research, Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland
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Cécile Pochon
6Université de Lorraine, CNRS, IMoPA, F-54000 Nancy, France
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Barbara Toffoli
3Center for Integrative Genomics, Genopode, Lausanne Faculty of Biology and Medicine CH-1015 Lausanne, Switzerland
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Jean-Yves Jouzeau
6Université de Lorraine, CNRS, IMoPA, F-54000 Nancy, France
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Federica Gilardi
3Center for Integrative Genomics, Genopode, Lausanne Faculty of Biology and Medicine CH-1015 Lausanne, Switzerland
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Serge Ferrari
7Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, Geneva 14, Switzerland
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Nicolas Bonnet
7Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, Geneva 14, Switzerland
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Claudine Blin-Wakkach
1CNRS UMR7370, Laboratoire de PhysioMédecine Moléculaire, Nice, France
2Université Côte d'Azur, Nice, France
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Béatrice Desvergne
3Center for Integrative Genomics, Genopode, Lausanne Faculty of Biology and Medicine CH-1015 Lausanne, Switzerland
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  • For correspondence: david.moulin@univ-lorraine.fr
David Moulin
6Université de Lorraine, CNRS, IMoPA, F-54000 Nancy, France
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  • For correspondence: david.moulin@univ-lorraine.fr
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Summary

Long bones from mammals host blood cell formation and contain multiple cell types, including adipocytes. Physiological functions of bone marrow adipocytes are poorly documented. Herein, we used adipocyte-deficient PPARγ-whole body null mice to investigate the consequence of total adipocyte deficiency on bone homeostasis in mice. We first highlight the dual bone phenotype of PPARγ null mice: on the one hand the increase bone formation and subsequent trabecularization extending in the long bone diaphysis, due to the well-known impact of PPARγ deficiency on osteoblasts formation and activity; on the other hand, an increased osteoclastogenesis in the cortical bone. We then further explore the cause of this unexpected increased osteoclastogenesis using two independent models of lipoatrophy, which recapitulated this phenotype. This demonstrates that hyperosteoclastogenesis is not intrinsically linked to PPARγ deficiency, but is a consequence of the total lipodystrophy. We further showed that adiponectin, a cytokine produced by adipocytes and mesenchymal stromal cells is a potent inhibitor of osteoclastogenesis in vitro and in vivo. Moreover, pharmacological activation of adiponectin receptors by the synthetic agonist AdipoRon inhibits mature osteoclast activity both in mouse and human cells by blocking podosome formation through AMPK activation. Finally, we demonstrated that AdipoRon treatment blocks bone erosion in vivo in a murine model of inflammatory bone loss, providing potential new approaches to treat osteoporosis.

Competing Interest Statement

The authors have declared no competing interest.

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Posted November 15, 2020.
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Adipose-tissue derived signals control bone remodelling
Maria-Bernadette Madel, He Fu, Dominique D. Pierroz, Mariano Schiffrin, Carine Winkler, Anne Wilson, Cécile Pochon, Barbara Toffoli, Jean-Yves Jouzeau, Federica Gilardi, Serge Ferrari, Nicolas Bonnet, Claudine Blin-Wakkach, Béatrice Desvergne, David Moulin
bioRxiv 2020.03.02.972711; doi: https://doi.org/10.1101/2020.03.02.972711
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Adipose-tissue derived signals control bone remodelling
Maria-Bernadette Madel, He Fu, Dominique D. Pierroz, Mariano Schiffrin, Carine Winkler, Anne Wilson, Cécile Pochon, Barbara Toffoli, Jean-Yves Jouzeau, Federica Gilardi, Serge Ferrari, Nicolas Bonnet, Claudine Blin-Wakkach, Béatrice Desvergne, David Moulin
bioRxiv 2020.03.02.972711; doi: https://doi.org/10.1101/2020.03.02.972711

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