Article
Divergent Effects of Free Fatty Acids on Cells of Bone Metabolism
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Published: | August 29, 2016 |
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Background: Obesity is associated with an increased risk of osteoarthritis also in non-weight bearing joints and increased amounts of visceral fat are associated with lower bone density. Furthermore, chronically elevated free fatty acid (FFA) serum levels are linked to a number of inflammatory cardiovascular and metabolic diseases. These observations suggest that FFA may also play a role in inflammation-related bone loss. The influence of FFA on cells of bone metabolism however has not been investigated yet. We analyzed the effect of FFA on osteoblasts and osteoclasts in the context of rheumatic diseases.
Methods: Primary osteoblasts were isolated from cancellous bone of rheumatoid arthritis (RA) and osteoarthritis (OA) patients undergoing knee joint surgery. Osteoblasts were stimulated with palmitic acid (PA) as a saturated and linoleic (LA) acid as an unsaturated FFA. Immunoassays were used to quantify protein secretion. mRNA expression was quantified by real-time PCR. Mineralization activity was analyzed by alizarin red S staining of mineralized matrix. Osteoclastogenesis of monocytic precursor cells was quantified by counting the number of differentiated osteoclasts defined as TRAP-positive multinucleated cells. Toll-like receptors (TLR) 2 and 4 were blocked by neutralizing antibodies.
Results: Both PA and LA increased the secretion of the proinflammatory cytokine IL-6 (up to 9-fold) and the chemokines IL-8 (up to 221-fold), GRO-α and MCP-1. The extent of the response was highly dependent on the donor. Markers of osteoblast activity (ALP, collagen type I) and osteoblast differentiation (e.g. osteocalcin) as well as RANKL and OPG, mediators of osteoclastogenesis and osteoclast activity, were not affected by FFA at mRNA or protein level. The PA-induced IL-8 secretion could be significantly reduced by blocking TLR4 but not TLR2. RA osteoclasts responded to PA and LA stimulation with a decrease in the number of TRAP-positive multinucleated cells. However, markers of osteoclast activity (CLCN7, CTSK, TCIRG) remained unchanged.
Conclusion: The effect of FFA on cells of bone metabolism appears to be divergent. Their proinflammatory effect via osteoblasts could indirectly promote bone resorption, while the reduced formation of differentiated osteoclasts might contribute to an increase in bone density.