Details

Autor(en) / Beteiligte

• Wauquier, Fabien
• Philippe, Claire
• Léotoing, Laurent
• Mercier, Sylvie
• Davicco, Marie-Jeanne
• Lebecque, Patrice
• Guicheux, Jérôme
• Pilet, Paul
• Miot-Noirault, Elisabeth
• Poitout, Vincent
• Alquier, Thierry
• Coxam, Véronique
• Wittrant, Yohann

Titel

The Free Fatty Acid Receptor G Protein-coupled Receptor 40 (GPR40) Protects from Bone Loss through Inhibition of Osteoclast Differentiation

Ist Teil von

• The Journal of biological chemistry, 2013-03, Vol.288 (9), p.6542-6551

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2013

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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. Background: Long chain fatty acids have been shown to activate the membrane-bound receptor GPR40. Results: GPR40 agonist alters bone-resorbing cell differentiation through inhibition of the NF-κB system. Conclusion: GPR40 exerts protective effects in vivo on bone tissue. Significance: GPR40 is a nutritional and therapeutic target opening up new avenues for clinical investigations in terms of metabolic and age-related bone disorders.