Adipose-tissue derived signals control bone remodelling.

Long bones from mammals host blood cell formation and contain many multiple cell types, including adipocytes. Excessive presence of adipocytes in bone marrow is associated with pathological conditions such as age-related osteoporosis or marrow aplasia induced by irradiation or chemotherapy. However, physiological functions of bone marrow adipocytes are poorly documented. Here, we investigated the consequence of total adipocyte deficiency on bone homeostasis in mice. By generating adipocyte-deficient mice using PPARlower case Greek gamma; deletion, we found that lipoatrophy leads to dramatic alterations of trabecular and cortical femoral bone. Cortical bone is extremely porous and poorly defined due to the excessive presence of active bone-resorbing osteoclasts. Hence, our observation demonstrates that osteoclast formation occurs in the absence of PPARlower case Greek gamma; despite its supposed role in osteoclastogenesis. We found that two independent models of lipoatrophy recapitulated this phenotype, demonstrating that hyperosteoclastogenesis is not linked to intrinsic PPARlower case Greek gamma; deficiency. 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. Furthermore, pharmacological activation of adiponectin receptors by the synthetic agonist AdipoRon is able to block mature osteoclast activity both in mouse and human by blocking podosome formation. Mechanistically, we demonstrated involvement of AMPK activation in the adiponectin-inhibiting action on mature osteoclasts, thereby demonstrating that even fully differentiated and active, osteoclasts are sensitive to adipose-derived signals. Lastly, we showed that AdipoRon inhibits bone erosion in vivo in a murine model of inflammatory bone loss. Collectively, these data reveal that adiponectin-producing cells are key regulators of bone homeostasis, and that preserving functional bone marrow adiponectin pathway can improve bone integrity in the context of metabolic and inflammatory disorders.