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  • Introduction Osteoclasts are large multinuclear cells

    2022-07-29

    Introduction Osteoclasts are large, multinuclear SB525334 that are responsible for the resorption (breakdown) of bone [1]. Together with osteoblasts, the bone forming cell, they maintain the integrity of the skeleton through constant resorption and repair of bone. Osteoclast precursors of monocytic lineage fuse when exposed to the osteoblast derived factors, receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony stimulating factor (M-CSF). RANKL binds to its receptor RANK on osteoclast precursors leading to the recruitment of tumor necrosis factor receptor associated factor 6 (TRAF6) and the formation of the transforming growth factor-β activated kinase 1 (TAK1)-TAK1 binding protein (TAB1) complex [2]. This activates the mitogen activated protein kinase (MAPK) and NF-κB signalling pathways, resulting in the activation of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), the key regulator of osteoclastogenesis [3,4]. MAPK signalling involves the phosphorylation of p38, JNK-1 and ERK-1 which activates nuclear targets leading to NFATc1 up-regulation [4]. NF-κB signalling begins with the phosphorylation of inhibitory kappa kinase (IKK), which leads to the phosphorylation and degradation of inhibitor of κB (IκB). This frees NF-κB to translocate into the nucleus and activate nuclear targets further amplifying NFATc1 expression. Osteoblasts are mononuclear cells that originate from mesenchymal stems cells (MSCs) [5]. Osteoblasts are responsible for laying down new, mineralised bone after resorption. Runt-related transcription factor 2 (Runx2) expression is the earliest recognized event during osteoblast formation [6]. Runx2 up-regulates osteoblast specific genes such as alkaline phosphatase (ALP), collagen type 1 alpha 1 (COL1A1) and bone sialoprotein (BSP) [6]. Osteoblasts produce RANKL and M-CSF to regulate osteoclast differentiation. Osteoblasts further produce osteoprotegerin (OPG), which acts as a decoy receptor to RANKL and prevents RANKL binding to RANK [7]. In this way osteoblasts can control osteoclastic resorption and maintain the balance between resorption and formation. To ensure that neither resorption nor formation is excessive, the continuous activity of both osteoclasts and osteoblasts is tightly coupled in a process known as the bone remodelling cycle. Disruption of the bone remodelling cycle underlies several bone degenerative diseases such as osteoporosis. For several years, unsaturated fatty acids (UFAs) have been studied for their beneficial effects on bone. Communities that consume high amounts of fish oils rich in ω−3 LCPUFAs have been shown to have lower incidences of osteoporosis [[8], [9], [10]]. However, much of the underlying mechanisms still remain unclear. We have previously reported that the ω−6 poly-UFA (PUFA), arachidonic acid (AA), the ω−3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the ω−7 mono-UFA (MUFA), palmitoleic acid (PLA), can inhibit osteoclastogenesis and bone resorption, in vitro [[11], [12], [13]]. Drosatos-Tampakaki et al. have noted similar inhibitory effects of the ω−9 MUFA, oleic acid (OA), on osteoclast formation and function [14]. DHA, EPA and OA have further been shown to increase gene expression of osteoblast markers in vitro [[15], [16], [17]]. This may indicate a common mechanism of action for these UFAs. Free fatty acid receptor 4 (FFAR4) is a G-protein coupled receptor (GPR) expressed throughout the body, including on osteoclasts and osteoblasts [18]. It is known to bind medium and long chain UFAs and therefore offers a potential as the mediator for the effects of UFAs in bone cells. FFAR4 (also known as GPR120) activation can lead to either Gαq or β-arrestin 2 (βarr2) signalling. Gαq signalling results in an increase in intracellular calcium and promotes cell growth [19]. βarr2 signalling prevents the formation of the TAK1-TAB1 complex and thereby offers a promising mediator for the anti-osteoclastogenic effects of UFAs [20]. Taludukar et al. have shown that FFAR4 agonists are “functionally selective” and whether stimulation of FFAR4 will favour the Gαq or βarr2 pathway can be unique for different cell types [21]. Therefore, the aim of this study was to determine whether FFAR4 plays a role in the activity of different classes of UFAs on bone cells.