Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 9, Pages 6542-6551Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.429084
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- Canadian Institutes of Health Research [MOP 177381]
- Canadian Diabetes Association
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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-kappa B ligand (RANKL)-induced osteoclast differentiation occurred via the inhibition of the nuclear factor kappa B (NF-kappa B) signaling pathway as demonstrated by decrease in gene reporter activity, inhibitor of kappa B kinase (IKK-/-) activation, inhibitor of kappa B (IkB alpha) 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.
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