Lubricin/Proteoglycan 4 binds to and regulates the activity of Toll-Like Receptors In Vitro.
Lubricin/Proteoglycan 4 binds to and regulates the activity of Toll-Like Receptors In Vitro.
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DOI：
10.1038/srep18910
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发表时间：
2016-01-11
影响因子：
4.6
通讯作者：
Krawetz RJ
中科院分区：
文献类型：
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作者：
Iqbal SM;Leonard C;Regmi SC;De Rantere D;Tailor P;Ren G;Ishida H;Hsu C;Abubacker S;Pang DS;Salo PT;Vogel HJ;Hart DA;Waterhouse CC;Jay GD;Schmidt TA;Krawetz RJ
蛋白多糖4(PRG4/润滑素)由驻留在关节软骨和滑膜关节内的细胞分泌。润滑素可能通过与CD44的相互作用在调节炎症反应中发挥作用。这促使我们研究润滑剂是否可以通过与Toll样受体(TLRs)的相互作用在炎症/免疫调节中发挥更大的作用。利用高表达TLR 2、4或5的人胚胎肾(HEK)细胞和表面等离子共振技术检测全长重组人润滑素是否能够与TLR结合并激活TLR。原代培养的人滑膜成纤维细胞也用流式细胞仪和Luminex多重ELISA进行检测。采用大鼠骨关节炎(OA)失稳模型来确定注射中的润滑剂是否能够调节体内的疼痛和/或炎症。润滑素可以结合并调节TLRs的活性，导致炎症信号的下游变化，而不依赖于HA。我们在体内通过关节内注射润滑剂在大鼠骨关节炎模型中证实了这些发现，在该模型中观察到全身炎症信号的抑制和疼痛的减轻。无论是在体内平衡状态下，还是在组织损伤状态下，润滑素都在调节炎症环境中发挥着重要作用。
Proteoglycan 4 (PRG4/lubricin) is secreted by cells that reside in articular cartilage and line the synovial joint. Lubricin may play a role in modulating inflammatory responses through interaction with CD44. This led us to examine if lubricin could be playing a larger role in the modulation of inflammation/immunity through interaction with Toll-like receptors (TLRs). Human Embryonic Kidney (HEK) cells overexpressing TLRs 2, 4 or 5 and surface plasmon resonance were employed to determine if full length recombinant human lubricin was able to bind to and activate TLRs. Primary human synovial fibroblasts were also examined using flow cytometry and Luminex multiplex ELISA. A rat destabilization model of osteoarthritis (OA) was used to determine if lubricin injections were able to regulate pain and/or inflammation in vivo. Lubricin can bind to and regulate the activity of TLRs, leading to downstream changes in inflammatory signalling independent of HA. We confirmed these findings in vivo through intra-articular injections of lubricin in a rat OA model where the inhibition of systemic inflammatory signaling and reduction in pain were observed. Lubricin plays an important role in regulating the inflammatory environment under both homeostatic and tissue injury states.