Abstract
BackgroundCurcumin 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).MethodsExpression 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.ResultsBoth 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.ConclusionThis study provides the first evidence that curcumin significantly slows OA disease progression and exerts a palliative effect in an OA mouse model.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1025-y) contains supplementary material, which is available to authorized users.
Highlights
Curcumin has been shown to have chondroprotective potential in vitro
As curcumin was localized within the infrapatellar fat pad (IPFP), we examined the effect of curcumin nanoparticle topical treatment on the gene expression profile of pro-inflammatory mediators in the IPFP, which have been shown to have a significant impact on cartilage homeostasis and OA [41,42,43]
We showed that oral or topical administration of curcumin immediately after destabilization of the medial meniscus (DMM) significantly slowed or delayed the initiation and progression of OA in mice. This was indicated by less cartilage erosion and proteoglycan loss, reduced synovitis and subchondral plate thickness, reduced degradation of type II collagen and aggrecan, and lower expression of matrix metalloproteinase (MMP)-13 and ADAMTS5 following curcumin treatment compared to vehicle controls
Summary
Curcumin has been shown to have chondroprotective potential in vitro. its effect on disease and symptom modification in osteoarthritis (OA) is largely unknown. While current pharmacologic treatments such as analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) provide symptomatic relief, such as relieving pain, they do not exert a clear clinical effect on OA disease prevention or modification [3]. Evidence from several recent in vitro studies suggests that curcumin may exert a chondroprotective effect through actions such as antiinflammatory, anti-oxidative stress, and anti-catabolic activity that are critical for mitigating OA disease pathogenesis and symptoms. Curcumin, by inhibiting the activator protein 1 (AP-1) pathway [14] and nuclear factor kappa B (NF-kB) activation [14,15,16], suppresses the gene expression of a number of matrix metalloproteinases (MMPs), which play critical roles in the breakdown of the cartilage extracellular matrix [7, 14,15,16,17]
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