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Wauquier F.,French National Institute for Agricultural Research | Wauquier F.,Clermont University | Wauquier F.,Laboratoire dIngenierie Osteo Articulaire et Dentaire | Philippe C.,French National Institute for Agricultural Research | And 28 more authors.
Journal of Biological Chemistry | Year: 2013

The mechanisms linking fat intake to bone loss remain unclear. By demonstrating the expression of the free fatty acid receptor G-coupled protein receptor 40 (GPR40) in bone cells, we hypothesized that this receptor may play a role in mediating the effects of fatty acids on bone remodeling. Using micro-CT analysis, we showed that GPR40-/- mice exhibit osteoporotic features suggesting a positive role of GPR40 on bone density. In primary cultures of bone marrow, we showed that GW9508, a GRP40 agonist, abolished bone-resorbing cell differentiation. This alteration of the receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation occurred via the inhibition of the nuclear factor κB (NF-κB) signaling pathway as demonstrated by decrease in gene reporter activity, inhibitor of κB kinase (IKKα/β) activation, inhibitor of κB (IkBα) phosphorylation, and nuclear factor of activated T cells 1 (NFATc1) expression. The GPR40-dependent effect of GW9508 was confirmed using shRNA interference in osteoclast precursors and GPR40-/- primary cell cultures. In addition, in vivo administration of GW9508 counteracted ovariectomy-induced bone loss in wild-type but not GPR40-/- mice, enlightening the obligatory role of the GPR40 receptor. Then, in a context of growing prevalence of metabolic and age-related bone disorders, our results demonstrate for the first time in translational approaches that GPR40 is a relevant target for the design of new nutritional and therapeutic strategies to counter bone complications. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Gautier H.,Laboratoire dIngenierie Osteo Articulaire et Dentaire | Gautier H.,University of Nantes | Chamblain V.,Laboratoire dIngenierie Osteo Articulaire et Dentaire | Weiss P.,Laboratoire dIngenierie Osteo Articulaire et Dentaire | And 3 more authors.
Journal of Materials Science: Materials in Medicine | Year: 2010

Calcium phosphate substitutes drug delivery systems are well known substances used in minor bone void-filling to release their therapeutic agent in situ. Few studies associating anaesthetics and analgesics have been performed to date. The aim of this work was to study the association of the analgesic, morphine, and the local anaesthetic, lidocaine, with a calcium deficient apatite matrix. Three types of biomaterials i.e. powders, granules and blocks, were prepared by isostatic compression, wet granulation and a combination of the two, evaluated and compared. The chemical structure of the associated therapeutic agent was studied and the characteristics of the drug delivery systems were appraised in terms of drug release. The integrity of the lidocaine hydrochloride structure, as determined by RMN 1H, was confirmed regardless of the formulation technique used (isostatic compression or wet granulation). However, analyses of morphine hydrochloride by RMN 1H revealed slight structural modifications. The association and formulation techniques that were used made it possible to obtain an in vitro release time varying from 1 to 4 days for lidocaine hydrochloride and from 1 to 3 days for morphine hydrochloride. © Springer Science+Business Media, LLC 2010.

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