Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, 110000, China.
Medical Research Center/Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Shenyang, 110000, China.
Biomed Pharmacother. 2021 Mar;135:111199. doi: 10.1016/j.biopha.2020.111199. Epub 2021 Jan 2.
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)-1β-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-1β-treated rat chondrocytes by promoting the phosphorylation of 5' AMP-activated protein kinase (AMPK). Our in vitro findings revealed that d-mannose delayed IL-1β-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.
骨关节炎（OA）是一种异质性疾病，由于涉及 OA 发病机制的调控网络的复杂性，尤其是在软骨退变方面，因此一直难以治疗。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 细胞来减轻骨质流失和抑制免疫病理学；然而，D-甘露糖在 OA 相关的软骨退变中的作用尚不清楚。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，在白细胞介素（IL）-1β处理的大鼠软骨细胞中孵育 D-甘露糖可通过提高细胞增殖、强烈激活自噬、减少凋亡和下调分解代谢来抑制 OA 退变。此外，对碘乙酸盐（MIA）处理的大鼠进行口服灌胃 D-甘露糖给药，结果表明，中剂量（1.25g/kg/天）而非高剂量或低剂量的 D-甘露糖可抑制 OA 进展并减轻 OA 发展，这基于较低的软骨宏观评分、较低的软骨和滑膜组织学评分、强烈激活自噬和下调分解代谢。就下游机制而言，我们表明 D-甘露糖可能通过促进 5' AMP 激活的蛋白激酶（AMPK）的磷酸化来激活 IL-1β处理的大鼠软骨细胞中的自噬，从而减轻 OA 退变。我们的体外研究结果表明，D-甘露糖通过 AMPK 通路增强自噬激活，从而延迟 IL-1β诱导的大鼠软骨细胞 OA 退变。此外，体内结果表明，中剂量的 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，是 OA 的一种潜在的疾病修饰药物和新型治疗剂。
