MATOs

Research themes

Our unit has been interested for many years in exploring fundamental aspects of skeletal functions through the study of in vitro and in vivo bone cells alterations models . Bone remodeling is a tightly controlled mechanism in which osteoblasts (OB), the cells in charge of bone construction, osteoclasts (OC), the ones in charge of bone resorption, and osteocytes (OST), the mecanosensors imbedded in the bone matrix, are the main actors.
The first axis developed in our team regards the effect of aging on bone tissue. In bone, aging induces an imbalance favoring bone resorption over formation, leading to osteoporosis. In addition to physiological aging, some environmental pollutants can accelerate aging. Among them, natural uranium which can be ingested at low doses in food and drinking water, has been shown to inhibit bone formation. In this context, the goal of our project is to determine the role of autophagy in OB in normal and pathological (osteoporosis / chronic uranium exposure) conditions. We’ve been first focusing on the role of autophagy in OB during normal aging. Using knockdown of autophagy-essential genes and OB-specific autophagy-deficient mice, we’ve demonstrated that autophagy deficiency in OB reduces mineralization capacity and results in increased oxidative stress and receptor activator of NF-kB (RANKL) secretion, favoring generation of osteoclasts, the cells specialized in bone resorption. In vivo, we observed a 50% reduction in trabecular bone mass in OB-specific autophagy-deficient mice. Our current work suggests that autophagy could be a new therapeutic target in osteoporosis. In addition, we are presently analyzing the consequences in bone matrix composition of an OB autophagy deficiency using proteomic approaches. Regarding the effect of natural uranium on bone, our results indicate that this metal can alter OB functions and is able to trigger autophagy.

The second axis involving autophagy regards bone tumors or osteosarcoma. Osteosarcoma is a highly metastatic mesenchymal tumor in which cancer cells produce osteoid, the organic extracellular matrix of bone, often associated with osteolytic lesions. Currently, the use of chemotherapy in combination with aggressive surgery has improved the long-term survival in these patients to 60%. However, despite intensive efforts, 40% of osteosarcoma patients still die of their disease.
It has recently been suggested that tumor persistence and recurrence could be due to the presence of a rare population of cells within the tumor mass with stem cell-like properties called “cancer stem cells” (CSCs). These cells exhibit extensive capability of self-renewal, are able to fuel tumor growth and are likely to be more resistant to radio- and chemotherapy. CSCs have recently been evidenced in solid tumors from various origins including bone and appear as a new therapeutic target. CSCs are submitted to stressful conditions such as hypoxia and nutrient limitation and are expected to be highly dependent on autophagy for their survival. In this project, we’re analyzing autophagy in CSCs and their parental cell lines, as well as the potential toxicity of different autophagy modulators. In addition, we compare the properties of autophagy-deficient and competent CSCs to elucidate the role of this cellular process in osteosarcoma and potentially identify new therapeutic targets in this pathology.

Publications

– Pierrefite-Carle V, Santucci-Darmanin S, Breuil V, Camuzard O., Carle GF. Autophagy in bone: self-eating to stay in balance. Ageing Res Rev. 2015 In press.
– Nollet M, Santucci-Darmanin S, Breuil V, Al-Sahlanee R, Cros C, Topi M, Momier D, Samson M, Pagnotta S, Cailleteau L, Battaglia S, Farlay D, Dacquin R, Barois N, Jurdic P, Boivin G, Heymann D, Lafont F, Lu SS, Dempster DW, Carle GF, Pierrefite-Carle V. Autophagy in osteoblasts is involved in mineralization and bone homeostasis. Autophagy. 2014;10(11):1965-77.
– Mouline CC, Beranger GE, Schmid-Antomarchi H, Quincey D, Momier D, Boukhechba F, Carle GF, Rochet N, Scimeca JC. Monocytes differentiation upon treatment with a peptide corresponding to the C-terminus of activated T cell-expressed Tirc7 protein. J Cell Physiol. 2012;227(8):3088-98.
– Breuil V, Amri EZ, Panaia-Ferrari P, Testa J, Elabd C, Albert-Sabonnadière C, Roux CH, Ailhaud G, Dani C, Carle GF, Euller-Ziegler L. Oxytocin and bone remodelling: relationships with neuropituitary hormones, bone status and body composition. Joint Bone Spine. 2011;78(6):611-5.
– Mansour A, Anginot A, Mancini SJ, Schiff C, Carle GF, Wakkach A, Blin-Wakkach C. Osteoclast activity modulates B-cell development in the bone marrow. Cell Res. 2011 Jul;21(7):1102-15.
– Breuil V, Ticchioni M, Testa J, Roux CH, Ferrari P, Breittmayer JP, Albert-Sabonnadière C, Durant J, De Perreti F, Bernard A, Euller-Ziegler L, Carle GF. Immune changes in post-menopausal osteoporosis: the Immunos study. Osteoporos Int. 2010;21(5):805-14.
– Boukhechba F, Balaguer T, Michiels JF, Ackermann K, Quincey D, Bouler JM, Pyerin W, Carle GF, Rochet N. Human primary osteocyte differentiation in a 3D culture system. J Bone Miner Res. 2009;24(11):1927-35.
– Rochet N, Balaguer T, Boukhechba F, Laugier JP, Quincey D, Goncalves S, CARLE GF. Differentiation and activity of human preosteoclasts on chitosan enriched calcium phosphate cement. Biomaterials. 2009 Sep;30(26):4260-7.

Composition de l'équipe

Georges CARLE, DR2 CNRS
Sabine SANTUCCI-DARMANIN, CR1 CNRS
Valérie PIERREFITE-CARLE, CR1 INSERM
Michel SAMSON, CR1 INSERM
Véronique BREUIL, PU-PH Rhumatologie, CHU Nice
Olivier CAMUZARD, Interne Chirurgie CHU Nice, Doctorant
Lucile HURAULT, Doctorante
Tatiana GRITSAENKO, Assistant Ingénieur
Chantal CROS, Technicienne UNS
Colette RICORT, Secrétaire