Curcumin slows osteoarthritis progression and relieves osteoarthritis-associated pain symptoms in a post-traumatic osteoarthritis mouse model.
Curcumin slows osteoarthritis progression and relieves osteoarthritis-associated pain symptoms in a post-traumatic osteoarthritis mouse model.
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DOI：
10.1186/s13075-016-1025-y
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发表时间：
2016-06-03
影响因子：
4.9
通讯作者：
Sun HB
中科院分区：
文献类型：
--
作者：
Zhang Z;Leong DJ;Xu L;He Z;Wang A;Navati M;Kim SJ;Hirsh DM;Hardin JA;Cobelli NJ;Friedman JM;Sun HB
姜黄素已被证明在体外具有软骨保护潜力。然而，它对骨关节炎(OA)的疾病和症状改善的作用在很大程度上是未知的。本研究旨在确定姜黄素是否可以减缓内侧半月板失稳(DMM)小鼠的OA进展并减轻与OA相关的疼痛。用姜黄素和姜黄素纳米颗粒处理人原代软骨细胞，并用实时荧光定量聚合酶链式反应检测软骨降解相关基因的表达。接受DMM手术的小鼠口服姜黄素或局部给予姜黄素纳米粒，为期8周。通过Safranin O染色和国际骨关节炎研究学会(OARSI)评分，裂解聚集素和II型胶原的免疫组织化学染色以及基质金属蛋白酶-13和ADAMTS5的水平来评价软骨的完整性。根据组织学图像对滑膜炎和软骨下骨厚度进行评分。用von Frey法评估与骨性关节炎相关的疼痛和症状，以及包括行走距离和站立在内的运动行为。姜黄素和包裹姜黄素的纳米粒均抑制原代培养软骨细胞IL-1β和肿瘤坏死因子-α、基质金属蛋白酶1、3和13以及聚集酶ADAMTS5的表达，并上调软骨保护转录调节因子CITED2，在没有或存在IL-1β的情况下。口服姜黄素显著减缓了骨性关节炎疾病的进展，但对骨性关节炎的疼痛缓解无明显效果。在损伤的小鼠膝盖皮肤上局部给予姜黄素纳米粒后，在髌下脂肪垫(IPFP)中检测到姜黄素。与赋形剂治疗的对照组相比，局部治疗导致：(1)蛋白多糖丢失和软骨侵蚀减少，OARSI评分降低，(2)滑膜炎和软骨下板厚度减少，(3)关节软骨中II型胶原和aggrecan裂解表位的免疫化学染色减少，基质金属蛋白酶-13和ADAMTS5阳性的软骨细胞数量减少，(4)脂肪因子和促炎介质在IPFP中的表达减少。与口服姜黄素相比，局部应用姜黄素纳米粒减轻了与骨性关节炎相关的疼痛，这表明减少了触觉过敏并改善了运动行为。这项研究提供了第一个证据，证明姜黄素显著减缓了骨性关节炎的疾病进展，并在骨性关节炎小鼠模型中发挥了缓解作用。本文的在线版本(doi：10.1186/s1307510161025-y)包含补充材料，授权用户可以使用。
Curcumin has been shown to have chondroprotective potential in vitro. However, its effect on disease and symptom modification in osteoarthritis (OA) is largely unknown. This study aimed to determine whether curcumin could slow progression of OA and relieve OA-related pain in a mouse model of destabilization of the medial meniscus (DMM). Expression of selected cartilage degradative-associated genes was evaluated in human primary chondrocytes treated with curcumin and curcumin nanoparticles and assayed by real-time PCR. The mice subjected to DMM surgery were orally administered curcumin or topically administered curcumin nanoparticles for 8 weeks. Cartilage integrity was evaluated by Safranin O staining and Osteoarthritis Research Society International (OARSI) score, and by immunohistochemical staining of cleaved aggrecan and type II collagen, and levels of matrix metalloproteinase (MMP)-13 and ADAMTS5. Synovitis and subchondral bone thickness were scored based on histologic images. OA-associated pain and symptoms were evaluated by von Frey assay, and locomotor behavior including distance traveled and rearing. Both curcumin and nanoparticles encapsulating curcumin suppressed mRNA expression of pro-inflammatory mediators IL-1β and TNF-α, MMPs 1, 3, and 13, and aggrecanase ADAMTS5, and upregulated the chondroprotective transcriptional regulator CITED2, in primary cultured chondrocytes in the absence or presence of IL-1β. Oral administration of curcumin significantly reduced OA disease progression, but showed no significant effect on OA pain relief. Curcumin was detected in the infrapatellar fat pad (IPFP) following topical administration of curcumin nanoparticles on the skin of the injured mouse knee. Compared to vehicle-treated controls, topical treatment led to: (1) reduced proteoglycan loss and cartilage erosion and lower OARSI scores, (2) reduced synovitis and subchondral plate thickness, (3) reduced immunochemical staining of type II collagen and aggrecan cleavage epitopes and numbers of chondrocytes positive for MMP-13 and ADAMTS5 in the articular cartilage, and (4) reduced expression of adipokines and pro-inflammatory mediators in the IPFP. In contrast to oral curcumin, topical application of curcumin nanoparticles relieved OA-related pain as indicated by reduced tactile hypersensitivity and improved locomotor behavior. This study provides the first evidence that curcumin significantly slows OA disease progression and exerts a palliative effect in an OA mouse model. The online version of this article (doi:10.1186/s13075-016-1025-y) contains supplementary material, which is available to authorized users.