Modulation of Osteoclastogenesis by Fatty Acids

Abstract

Clinical studies have shown that total body fat mass is related to both bone density and fracture risk and that fat ingestion reduces bone turnover. These effects are at least partially mediated by endocrine mechanisms, but it is possible that lipids might act directly on bone. We assessed the effects of broad fractions of milk lipids in osteoblasts, bone marrow, and neonatal mouse calvariae. Several milk fractions and their hydrolysates inhibited osteoclastogenesis in bone marrow cultures, so we assessed the effects of free fatty acids in this model. Saturated fatty acids (0.1-10 microg/ml) inhibited osteoclastogenesis in bone marrow cultures and RAW264.7 cells. This effect was maximal for C14:0 to C18:0 fatty acids. The introduction of greater than 1 double bond abrogated this effect; omega3 and omega6 fatty acids had comparable low activity. Osteoblast proliferation was modestly increased by the antiosteoclastogenic compounds, ruling out a nonspecific toxic effect. Active fatty acids did not consistently change expression of receptor activator of nuclear factor-kappaB ligand or osteoprotegerin in osteoblastic cells nor did they affect the activity of key enzymes in the mevalonate pathway. However, receptors known to bind fatty acids were found to be expressed in osteoblastic (GPR120) and osteoclastic (GPR40, 41, 43, 120) cells. A synthetic GPR 40/120 agonist mimicked the inhibitory effects of fatty acids on osteoclastogenesis. These findings provide a novel link between lipid and bone metabolism, which might contribute to the positive relationship between adiposity and bone density as well as provide novel targets for pharmaceutical and nutriceutical development.

Saturated fatty acids enhance osteoclast survival

“…Contrary to our results, inhibition or no signifi cant effect of OC formation by SFA in murine macrophage cell line, RAW264.7 cells, has been reported ( 26,27 ). However, they did not distinguish the effect of SFA at specifi c stage.…”

Long-chain polyunsaturated fatty acids: Selected mechanisms of action on bone

“…In contrast to the work reporting effects of LCPUFAs on bone cells, Cornish et al [104] recently reported an effect of saturated fatty acids on osteoclastogenesis. They studied several short and medium chain fatty acids and stearic (C18:0) and palmitic acid (C16:0) exhibited a significant inhibitory effect on osteoclastogenesis.…”

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

“…Cornish et al (24) showed that RAW264.7 cells express both GPR120 and GPR40 at the mRNA levels and hypothesized a potential role of these receptors in the effects of saturated fatty acids on osteoclastogenesis. In addition, Oh et al (23) recently demonstrated that GPR120 was responsible for mediating docosahexaenoic acid anti-inflammatory properties in a macrophage …”

“…As bone tissues share common precursor cells with the hematopoietic lineage, GPR40 expression was investigated in bone cells (24,25). Indirect evidence in support for a role of GPR40 in fatty acid stimulation of bone formation was provided by Cornish et al, who observed that GPR40 is expressed in osteoclasts and that a GPR40 agonist mimics fatty acid inhibition of osteoclastogenesis (24). Mieczkowska et al recently confirmed the expression of GPR40 in bone cells and observed that down-regulation of GPR40 by RNA interference protects from thiazolidinedione-induced osteocyte apoptosis (25).…”