Hyperlipidemia and marrow fat are associated with lowering bone density in vivo, suggesting that lipid contributes to bone loss. Using bone marrow-derived macrophages, we investigated the effect of saturated fatty acids (SFA) on osteoclastogenesis. The level of free fatty acids and adiposity in bone marrow was significantly elevated in obese mice. SFA increased osteoclast (OC) survival by preventing apoptosis. SFA caused the production of MIP-1alpha and led to activation of nuclear factor (NF)-kappaB in the OC. The absence of Toll-like receptor 4 (TLR4) or myeloid differentiation factor 88 (MyD88) abolished the survival effect of SFA on OC.

Ovariectomy (OVX)-induced estrogen withdrawal resulted in both bone loss and an increase in fat. We observed elevated osteoclast (OC) formation by bone marrow-derived macrophages treated with medium conditioned by fats from OVX mice, but not from sham-operated mice. Fats from OVX mice expressed and secreted higher levels of monocyte chemoattractant protein-1 (MCP-1) than those from sham-operated mice. Increased fat resulting from estrogen deficiency is thus responsible for bone loss due to enhanced OC formation, which is, at least partly, a consequence of elevated MCP-1 production.

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