Department of Physiology, University of Pretoria, Pretoria 0001, South Africa.
School of Health Sciences, College of Health, Massey University, Palmerston North 4442, New Zealand.
Int J Mol Sci. 2019 Apr 11;20(7):1798. doi: 10.3390/ijms20071798.
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.
破骨细胞是体内唯一具有骨吸收功能的细胞，其过度活跃是骨质疏松症发展的关键。破骨细胞的形成是由核因子κB 受体激活剂配体（RANKL）信号通路介导的。已知不饱和脂肪酸（UFA）通过靶向 RANKL 信号通路来抑制破骨细胞的形成。然而，其作用机制尚不清楚。过氧化物酶体增殖物激活受体（PPARs）是一类核受体，有三种已知的亚型（PPAR-α、PPAR-β/δ 和 PPAR-γ），已知它们可以与 UFA 结合并在破骨细胞中表达。在这项研究中，我们旨在确定不同类型的 UFA 如何激活 PPARs，以及 PPAR 激活如何影响破骨细胞信号转导。将人 CD14+单核细胞接种到含有 RANKL 和巨噬细胞集落刺激因子（M-CSF）的聚类板中，并在 PPAR 激动剂或不同类型的 UFA 存在的情况下进行培养。所有的 PPAR 激动剂都被证明能上调其相应受体的活性。多不饱和脂肪酸（PUFAs）比单不饱和脂肪酸（MUFAs）更能上调 PPAR-α的活性，而 MUFAs 则更有利于 PPAR-β/δ 的激活。所有的 PPAR 激动剂都抑制了破骨细胞的形成。RANKL 信号通路的激活和关键破骨细胞基因的表达也被 PPAR 激动剂下调。这项研究揭示了 PPAR 激活可以通过调节 RANKL 信号转导来抑制破骨细胞的形成。
