D-Mannose suppresses osteoarthritis development in vivo and delays IL-1β-induced degeneration in vitro by enhancing autophagy activated via the AMPK pathway
D-Mannose suppresses osteoarthritis development in vivo and delays IL-1β-induced degeneration in vitro by enhancing autophagy activated via the AMPK pathway
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DOI：
10.1016/j.biopha.2020.111199
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发表时间：
2021-01-02
影响因子：
7.5
通讯作者：
Bai, Lunhao
中科院分区：
文献类型：
--
作者：
Lin, Zhiming;Miao, Jianing;Bai, Lunhao
骨关节炎（OA）是一种异质性疾病，由于OA发病机制中涉及的调控网络的复杂性，特别是在软骨退变方面，一直难以治疗。作为葡萄糖的C-2差向异构体，D-甘露糖可以通过上调调节性T细胞来减轻骨丢失并抑制免疫病理学;然而，D-甘露糖在OA相关软骨变性中的作用仍然未知。在这项研究中，我们研究了D-甘露糖在体外和体内对OA的软骨保护作用。我们发现，孵育白细胞介素（IL）-1 β-处理的大鼠软骨细胞与D-甘露糖抑制OA变性，通过提高细胞增殖，强烈激活自噬，减少凋亡，下调catalysts。此外，经口灌胃给予碘乙酸（MIA）处理的大鼠D-甘露糖显示，中位数（1.25 g/kg/天）而不是高或低剂量的D-甘露糖抑制了OA进展，并基于软骨的较低宏观评分、软骨和滑膜的组织学评分降低、自噬强烈激活和catalase下调而减弱了OA发展。在下游机制方面，我们发现D-甘露糖可能通过促进5'AMP活化蛋白激酶（AMPK）的磷酸化而激活IL-1 β处理的大鼠软骨细胞中的自噬，从而减轻OA变性。我们的体外研究结果表明，D-甘露糖通过AMPK途径增强自噬激活，从而延迟IL-1 β诱导的大鼠软骨细胞OA变性。此外，体内结果表明，中位剂量的D-甘露糖抑制MIA诱导的OA发展。这些结果表明，D-甘露糖具有软骨保护作用，代表了一种潜在的疾病改善药物和新的治疗剂的OA。
Osteoarthritis (OA) is a heterogeneous disease that is consistently difficult to treat due to the complexity of the regulatory network involved in OA pathogenesis, especially in terms of cartilage degeneration. As a C-2 epimer of glucose, D-mannose can alleviate bone loss and repress immunopathology by upregulating regulatory T cells; however, the role of D-mannose in OA-related cartilage degeneration remains unknown. In this study, we investigated the chondroprotective effect of D-mannose in vitro and in vivo on OA. We found that incubating interleukin (IL)-1 beta-treated rat chondrocytes with D-mannose restrained OA degeneration by elevating cell proliferation, strongly activating autophagy, reducing apoptosis, and downregulating catabolism. Additionally, oral gavage administration of D-mannose to monosodium iodoacetate (MIA)-treated rats revealed that a median (1.25 g/kg/day) rather than high or low dose of D-mannose suppressed OA progression and attenuated OA development based on lower macroscopic scores for cartilage, decreased histological scores for cartilage and synovium, strongly activated autophagy, and downregulated catabolism. In terms of a downstream mechanism, we showed that D-mannose might attenuate OA degeneration by activating autophagy in IL-1 beta-treated rat chondrocytes by promoting the phosphorylation of 5' AMP-activated protein kinase (AMPK). Our in vitro findings revealed that D-mannose delayed IL-1 beta-induced OA degeneration in rat chondrocytes by enhancing autophagy activation through the AMPK pathway. Furthermore, the in vivo results indicated that a median dose of D-mannose suppressed MIA-induced OA development. These results suggested that D-mannose exhibits chondroprotective effects and represents a potential disease-modifying drug and novel therapeutic agent for OA.