Oleate abrogates palmitate-induced lipotoxicity andpro-inflammatory response in human bone marrowderivemesenchymal stem cells and osteoblastic cells

Osteoporosis is a metabolic bone disease associated with unequilibrated bone remodeling resulting from decreased bone formation and/or increased bone resorption, leading to progressive bone loss. In osteoporotic patients, low bone mass is associated with an increase of bone marrow fat resulting from accumulation of adipocytes within bone marrow (BM). BM adipocytes are active secretory cells, releasing cytokines, adipokines and free fatty acids (FA) that influence the BM microenvironment and altered the biology of neighboring cells. Therefore, we examined the influence of palmitate and oleate, two highly prevalent FA in human organism and diet, on the function and survival of human mesenchymal stem cells (MSC) and MSC-derived osteoblastic cells. The saturated FA palmitate exerted a cytotoxic action via initiation of endoplasmic reticulum stress and activation of the NF-B and ERK pathways. In addition, palmitate induced a pro-inflammatory response, as determined by the upregulation of TLR4 expression as well as the increase of IL-6 and IL-8 expression and secretion. Moreover,weshowed that MSC-derived osteoblastic cells were more sensitive to lipotoxicity than undifferentiated MSC. The monounsaturated FA oleate fully neutralized palmitate-induced lipotoxicity by impairing activation of the pathways triggered by the saturated FA. Moreover, oleate promoted palmitate detoxification by fostering its esterification into triglycerides and storage in lipid droplets. Altogether, our data showed that physiological concentrations of palmitate and oleate differently modulated cell death and function in bone cells. We therefore propose that FA could influence skeletal health.