ECTS Abstracts (2015) 1 P144

Autophagy in Osteoblasts is Involved In Mineralisation and Bone Homeostasis

Valérie Pierrefite-Carle1, Marie Nollet1, Sabine Santucci-Darmanin1, Véronique Breuil1,2, Rasha Al-Sahlanee1, Michel Samson1, Sophie Pagnotta3, Séverine Battaglia4, Delphine Farlay5, Romain Dacquin6, Pierre Jurdic6, Georges Boivin5, Dominique Heymann4, Shi Shou Lu7, David Dempster7 & Georges F. Carle1

1UMR E4320 TIRO-MATOs, Université Nice Sophia Antipolis, Nice, France; 2Service de Rhumatologie – CHU de Nice, Nice, France; 3CCMA, Université Nice Sophia-Antipolis, Nice, France; 4INSERM UMR 957, Université de Nantes, Nantes, France; 5INSERM UMR 1033, Université de Lyon, Lyon, France; 6IGFL, Université de Lyon, CNRS, ENS Lyon, Lyon, France; 7Helen Hayes Hospital, West Havertsraw, New York, USA.

Autophagy is the major catabolic process of eukaryotic cells that degrades and recycles damaged macromolecules and organelles. During this process, the cytoplasmic material targeted to degradation is delivered to lysosomes upon sequestration within double-membraned vesicles called autophagosomes. Autophagosomes and their contents are cleared upon fusing with late endosomes or lysosomes, and products of these catabolic reactions can then re-enter anabolic and/or bioenergetic metabolisms. Autophagy occurs at low level in all cells to ensure the homeostatic turnover of long-lived proteins and organelles and is upregulated under stressful conditions. In the present work, we analysed the role of autophagy in osteoblasts (OB). We first show that the autophagic process is induced in OB during mineralisation. Then, using knockdown of autophagy-essential genes and OB-specific autophagy-deficient mice, we demonstrate that autophagy deficiency reduces mineralisation capacity. Moreover, our data suggest that autophagic vacuoles are used as vehicles in OB to secrete hydroxyapatite crystals. In addition, autophagy-deficient OB exhibit increased oxidative stress and receptor activator of NF-kB (RANKL) secretion, favouring generation of osteoclasts (OC), the cells specialised in bone resorption. In vivo, we observed a 50% reduction in trabecular bone mass in OB-specific autophagy-deficient mice. Taken together, our results show for the first time that autophagy in OB is involved both in the mineralisation process and in bone homeostasis. These findings are of importance for mineralised tissues which extends from corals to vertebrates and uncovers new therapeutics targets for calcified tissue related metabolic pathologies such as osteoporosis.

Disclosure: The authors declared no competing interests. This work was supported by grants from CNRS, CEA, The Societe Francaise de Rhumatologie, and Les Anges de Verre.