Curcumin slows osteoarthritis progression and relieves osteoarthritis-associated pain symptoms in a post-traumatic osteoarthritis mouse model

In this study we demonstrated the first evidence in vivo to show that oral and topical curcumin administration slows the progression of post-traumatic OA in the DMM mouse model. Specifically, we showed that oral or topical administration of curcumin immediately after 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 MMP-13 and ADAMTS5 following curcumin treatment compared to vehicle controls. The preventative and therapeutic potential of curcumin is extremely valuable, given about 50 % of patients who suffer joint injuries, such as anterior cruciate ligament tears, develop OA within 10–15 years [47], and that there is no disease-modifying therapy for OA [48].

Furthermore, we provide the first evidence of a palliative effect of curcumin encapsulated in custom-made nanoparticles applied topically to an osteoarthritic joint in mice. Mice with DMM treated with curcumin nanoparticles exhibited decreased sensitivity to mechanical stimuli and increased locomotor behavior (i.e., distance traveled and rearing) compared to vehicle-treated mice, suggesting an improvement in OA-related pain. The results are consistent with a recently randomized, double-blind, placebo-controlled trial, in which patients with OA receiving a curcuminoid had significantly lower scores on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Lequesne’s pain functional index than patients receiving a placebo [23].

There is currently no cure for OA or a therapeutic agent with proven evidence to slow or halt the progression of OA [49]. Treatments used to temporarily relieve pain in OA, such as NSAIDs, may also cause severe gastrointestinal, renal, and cardiovascular side effects after long-term use [49–51]. In addition, patients experiencing pain relief without a concurrent improvement in the disease itself may become less conscientious about protecting their diseased joints (such as by avoiding overuse), and may unknowingly exacerbate the progression of OA. On the other hand, an OA drug that halts the progression of OA but does not relieve OA-related pain may not be effective, as patient compliance would likely be low. Upon further validation in other animal models and clinical trials, the effects of curcumin in both disease and symptom modification make it an attractive potential therapeutic agent for OA.

While the etiologic and pathogenic mechanisms for both initiation and progression of OA are not clear, inflammation, over-activated catabolic activity and oxidative stress responses are considered to be common in both processes [2, 44, 52, 53]. The effects of curcumin on attenuating inflammation, formation of reactive oxygen species, and catabolic activity have been suggested in chondrocytes in vitro [7, 14–16, 18, 19], in human synovial fibroblasts and in collagen-induced arthritis in mouse models [7, 14–16, 18, 19]. Furthermore, Colitti et al have shown an anti-inflammatory effect of curcumin on the gene expression of peripheral white blood cells in dogs with OA [16]. Consistent with these studies, we demonstrated that curcumin, in both the non-encapsulated (Fig. 1) and encapsulated forms (Fig. 3) exerts broad chondroprotective effects in human primary chondrocytes by suppressing the expression of genes encoding inflammatory cytokines IL-1? and TNF-?, and cartilage-degrading enzymes from the MMP family, including MMP-1, MMP-3, and MMP-13. We also demonstrated for the first time that curcumin suppresses expression of aggrecanase ADAMTS5, a key proteinase in cartilage destruction during OA that primarily cleaves the aggrecan components of the cartilage extracellular matrix [54–56]. Curcumin also induces gene expression of CITED2, an MMP-repressing transcriptional regulator. We previously demonstrated that CITED2, in response to moderate mechanical loading, represses expression of MMP-1 and MMP-13 in vitro [57] and in vivo [26]. NF-kB is a key factor that triggers the expression of various genes implicated in cartilage destruction, synovial membrane inflammation, and bone resorption [58, 59]. As CITED2 may negatively regulate NF-kB activity in embryonic kidney cells [60], curcumin may exert its chondroprotective effects by suppressing NF-kB activity by upregulating CITED2.

It has been reported that curcumin is barely soluble in water and poor absorption is attained from the epithelial cells in the gastrointestinal tract. Rats given an oral dose of curcumin excreted 75 % in the feces unchanged, with less than 0.02 % recovered from the liver, kidney, and body fat [61]. However, several studies analyzing plasma levels of curcumin or its metabolites have detected curcumin, although only small amounts, following relatively high doses of oral administration in humans [62, 63]. In this study, we demonstrated that oral administration of curcumin exerted efficacy in slowing the progression of post-traumatic OA. However, a palliative effect was not observed in mice with OA induced by DMM when curcumin was administrated orally in this study. The data suggest orally delivered curcumin is unlikely to reach biologically/pharmacologically active concentrations in the serum, synovial fluid, or joint tissues, that are sufficient to mitigate OA-related pain [4]. Together, our observation further indicates that relieving pain and its symptoms may require higher levels of curcumin compared to those required for disease modification.

As topical administration is a patient-friendly drug delivery method in OA treatment, we examined the efficacy of topical administration of nanoparticles encapsulating curcumin in OA disease modification and symptom improvement in mice with OA induced by DMM. Topical application of curcumin nanoparticles was efficacious not only in OA disease modification (Fig. 5), but also in relieving OA-related pain (Fig. 7). The data indicate that the topical application of curcumin encapsulated within nanoparticles preserves the chondroprotective activity of curcumin, and may increase its bioavailability.

Pathological changes in DMM-induced OA, including cartilage destruction, synovitis, and subchondral bone thickening, are observed in human OA [32]. Our study shows that curcumin treatment via oral (Fig. 2) or topical administration (Fig. 5) significantly improved OA-related pathological changes in the synovium and subchondral bone, indicating that curcumin has comprehensive potential for the treatment of joint tissues in OA [2].

The IPFP is an adipose tissue located within the knee joint synovial capsule, which may contribute to low-grade inflammation and cartilage degeneration through the secretion of adipokines and pro-inflammatory mediators into the synovial joint [64, 65]. In this study, we demonstrated that topically applied curcumin was largely localized in the infrapatellar fat pad (Fig. 4a). We further demonstrated that this treatment led to reduced expression of adipokines and pro-inflammatory mediators in the fat pad (Fig. 4b). These data suggest curcumin may slow the disease progression in OA, at least in part, by mitigating the pro-inflammatory mediating effect of the IPFP on cartilage and articular joints.

In this study, we provide the first evidence to demonstrate the efficacy of curcumin in OA disease and symptom modification using a post-traumatic OA mouse model. In addition to traumatic joint injuries, other conditions such as mechanical overuse and aging are risk factors for OA [66, 67]. Evaluating the efficacy of curcumin in other relevant OA models such as overuse-induced OA and spontaneous OA, which represents age-related OA, will be of interest.