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Aix-en-Provence, France

Verron E.,University of Nice Sophia Antipolis | Verron E.,Graftys Inc. | Verron E.,French Institute of Health and Medical Research | Loubat A.,University Of Nice | And 7 more authors.
Biochemical Pharmacology | Year: 2012

We had previously reported that gallium (Ga) inhibited both the differentiation and resorbing activity of osteoclasts in a dose-dependent manner. To provide new insights into Ga impact on osteoclastogenesis, we investigated here the molecular mechanisms of Ga action on osteoclastic differentiation of monocytes upon Rankl treatment. We first observed that Ga treatment inhibited the expression of Rankl-induced early differentiation marker genes, while the same treatment performed subsequently did not modify the expression of late differentiation marker genes. Focusing on the early stages of osteoclast differentiation, we observed that Ga considerably disturbed both the initial induction as well as the autoamplification step of Nfatc1 gene. We next demonstrated that Ga strongly up-regulated the expression of Traf6, p62 and Cyld genes, and we observed concomitantly an inhibition of IκB degradation and a blockade of NFκB nuclear translocation, which regulates the initial induction of Nfatc1 gene expression. In addition, Ga inhibited c-Fos gene expression, and subsequently the auto-amplification stage of Nfatc1 gene expression. Lastly, considering calcium signaling, we observed upon Ga treatment an inhibition of calcium-induced Creb phosphorylation, as well as a blockade of gadolinium-induced calcium entry through TRPV-5 calcium channels. We identify for the first time Traf6, p62, Cyld, IκB, NFκB, c-Fos, and the calcium-induced Creb phosphorylation as molecular targets of Ga, this tremendously impacting the expression of the master transcription factor Nfatc1. In addition, our results strongly suggest that the TRPV-5 calcium channel, which is located within the plasma membrane, is a target of Ga action on human osteoclast progenitor cells. © 2011 Elsevier Inc. All Rights Reserved.

Verron E.,French Institute of Health and Medical Research | Verron E.,Graftys Inc. | Gauthier O.,French Institute of Health and Medical Research | Gauthier O.,British Petroleum | And 6 more authors.
Biomaterials | Year: 2010

Resorbable calcium phosphate (CaP) biomaterials have demonstrated considerable efficacy in bone reconstructive surgery. Furthermore, bisphosphonates (BPs) are well known anti-resorptive agents largely used in clinical treatments for osteoporosis. An injectable BP-combined CaP matrix has been developed in order to biologically reinforce osteoporotic bone by increasing the bone fraction and improving bone micro-architecture. Our previous in vitro studies have shown that CaP is effective for loading and releasing BPs at doses that can inhibit excessive bone resorption without affecting osteoblasts. In vivo studies in relevant animal models are necessary to explore the effect of our injectable BP-combined biomaterial on femur bone structure by performing three-dimensional microtomography analysis, histological studies and SEM observations. Firstly, in rat model, our BP-combined CaP matrix significantly improved the bone micro-architecture as compared to CaP alone. The implantation of the BP-loaded biomaterial within proximal femurs of osteoporotic ewes led to a significant increase in relative bone content and an improvement of its micro-architecture. These modifications were confirmed by histological and SEM observations, which revealed CaP granule resorption and new bone trabeculae formation. This approach could be considered in the future for preventing osteoporotic fractures that are preferentially localized in the proximal femur, vertebral bodies or wrist. © 2010 Elsevier Ltd.

Graftys Inc., University of Nantes and French National Center for Scientific Research | Date: 2010-03-03

The present invention relates to a galliated calcium-phosphate biomaterial comprising a gallium-doped phosphocalcic compound of formula (I): Ca(

University of Nantes and Graftys Inc. | Date: 2010-03-03

The present invention relates to a gallium-doped phosphocalcic compound of formula (I): Ca

Graftys Inc., University of Nantes and French National Center for Scientific Research | Date: 2014-11-14

The present invention relates to a macroporous, resorbable and injectable apatitic calcium-phosphate cement with a high compressive strength useful as bone cement and releasing a bone resorption inhibitor, preparation method and uses thereof.

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