Abstract
Osteoclasts are the sole bone resorbing cell in the body and their over activity is key in the development of osteoporosis. Osteoclastogenesis is mediated by receptor activator of nuclear factor κB ligand (RANKL) signalling pathways. Unsaturated fatty acids (UFA) are known to inhibit osteoclastogenesis by targeting RANKL signalling. However, the mechanisms of action remain unclear. Peroxisome proliferator activated receptors (PPARs) are a family of nuclear receptors, with three known isoforms (PPAR-α, PPAR-β/δ and PPAR-γ), that are known to bind UFAs and are expressed in osteoclasts. In this study, we aimed to determine how different families of UFAs activate PPARs and how PPAR activation influences osteoclast signalling. Human CD14+ monocytes were seeded into cluster plates with RANKL and macrophage colony stimulating factor (M-CSF) in the presence of PPAR agonists or different types of UFAs. All the PPAR agonists were shown to upregulate the activity of their respective receptors. Polyunsaturated fatty acids increased PPAR-α to a greater extent than monounsaturated fatty acids (MUFAs), which favoured PPAR-β/δ activation. All PPAR agonists inhibited osteoclastogenesis. The activation of RANKL signalling pathways and expression of key osteoclast genes were downregulated by PPAR agonists. This study reveals that PPAR activation can inhibit osteoclastogenesis through modulation of RANKL signalling.
Highlights
Osteoclasts are large multinucleated cells responsible for the resorption of bone [1]
We further aimed to investigate the effects of Peroxisome proliferator activated receptors (PPARs) activation on RANKL signalling in osteoclasts
CD14+ monocytes were seeded into 6-well plates in complete alpha-MEM to attach overnight before cells were exposed to PPAR agonists (10 μM), arachidonic acid (AA) (40 μM), docosahexaenoic acid (DHA) (40 μM), eicosapentaenoic acid (EPA) (40 μM), palmitoleic acid (PLA) (100 μM) or oleic acid (OA) (100 μM) in the presence of RANKL and macrophage colony stimulating factor (M-CSF)
Summary
Osteoclasts are large multinucleated cells responsible for the resorption of bone [1]. RANKL signalling offers up a potential target to inhibit osteoclast formation and activity and possibly treat bone degenerative diseases. PPAR-α and PPAR-β/δ dual agonists have been shown to lower triglycerides and low density lipoprotein cholesterol with concurrent insulin sensitising effects [13] These results suggest that dual agonists may have potential in the treatment of metabolic syndrome, further clinical studies are necessary [14]. Unsaturated fatty acids (UFAs) are natural ligands of PPARs, and PPARs have been suggested as potential targets through which several UFAs exert their bone protective effects [26] Both monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) are known to activate PPARs. The ω-7 MUFA palmitoleic acid (PLA) has been shown to induce PPAR-γ activity in human adipocytes to a greater extent than the PPAR-γ agonist, rosiglitazone [27]. Nree2it)h. er PPAR agonists nor any of the UFAs showed any effect on cell viability in the human CD14+ monocytes (Figure 2)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
