PT  - JOURNAL ARTICLE
AU  - Maria-Bernadette Madel
AU  - He Fu
AU  - Dominique D. Pierroz
AU  - Mariano Schiffrin
AU  - Carine Winkler
AU  - Anne Wilson
AU  - Cécile Pochon
AU  - Barbara Toffoli
AU  - Jean-Yves Jouzeau
AU  - Federica Gilardi
AU  - Serge Ferrari
AU  - Nicolas Bonnet
AU  - Claudine Blin-Wakkach
AU  - Béatrice Desvergne
AU  - David Moulin
TI  - Adipose-tissue derived signals control bone remodelling
AID  - 10.1101/2020.03.02.972711
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.03.02.972711
4099  - http://biorxiv.org/content/early/2020/11/15/2020.03.02.972711.short
4100  - http://biorxiv.org/content/early/2020/11/15/2020.03.02.972711.full
AB  - 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 StatementThe authors have declared no competing interest.