Molecular targets of natural health products in arthritis

Patients with rheumatoid arthritis (RA) and osteoarthritis (OA) consume 'natural health products' (NHPs) whose therapeutic efficacy, toxicity and mechanisms of action are poorly understood. In a previous issue of Arthritis Research and Therapy, Haqqi and colleagues characterized IL-1-activated mitogen-activated protein kinase kinase 3 (MKK3) and p38-mitogen-activated protein kinase (MAPK) isoforms in human OA chondrocytes. The cartilageprotective mechanisms of pomegranate extract involve diminishing MKK3-activated p38α, JNK, NF-κB and Runx2 pathways, which regulate inflammatory proteins and cartilage-destroying proteases. Epigallocatechin- 3-gallate, resveratrol, curcumin and other NHP active ingredients suppress multiple inflammatory and catabolic molecular mediators of arthritis. Non-toxicity, reduced severity and incidence of arthritis in animal models warrant testing NHP active ingredients for preventing human OA and RA.

Considering the non-toxicity of PE in chondrocytes and its eff ectiveness in RA and OA models, identifying precise pomegranate active ingredients, their synergistic eff ects and utility for preventing or reducing human OA and RA through clinical trials is warranted. Epidemiological studies on non-consuming and pomegranateconsum ing populations for incidence of arthritis may also be useful. One should also analyze potential pharmaco logical drug-PE interactions.
Th e anti-arthritic eff ects of green tea are attributed to the multiple activities of non-toxic epigallocatechin-3gallate (EGCG). It suppresses IL-1-induced glycosaminoglycan release from cartilage by inhibiting ADAMTS, MMP-1 and MMP-13 expression through preferentially blocking NF-κB activity in chondrocytes. EGCG also inhibits IL-1-stimulated inducible nitric oxide synthase (iNOS), nitric oxide and JNK activities, which mediate cartilage degradation. In RA synovial fi broblasts, EGCG inhibits TNF-α-induced MMP-1, MMP-3, ERK (extracellular signal-regulated kinase), p38, JNK and AP-1 activities. EGCG sensitizes RA fi broblasts to TNF-αinduced caspase-3-mediated apoptosis by blocking Akt and NF-κB cell survival pathways. EGCG also inhibits IL-6 receptor-induced MMP-2, increases gp130 receptor in fi broblasts and ameliorates adjuvant-induced rat arthritis. EGCG suppresses osteoclast-specifi c, NF-ATc1 and RA-associated bone resorption and ameliorates mouse arthritis. It inhibited oncostatin M-stimulated CCL2 chemokine expression in human osteoblasts and reduced severity of collagen-induced arthritis. Th ese in vitro and in vivo studies suggest that EGCG could reduce synovial hyperplasia, cartilage degradation and bone resorption by modulating multiple targets in joints [9]. Despite its apparent safety in clinical trials of other diseases, its potential for causing apoptosis in chondrocytes should be tested further.
Resveratrol from grapes displays anti-infl ammatory and chondroprotective activities by increasing proteoglycan synthesis and chondrocyte proliferation and by suppressing IL-1, reactive oxygen species, p53-induced apoptosis, leukotriene B4, prostaglandin E2 synthesis and MMPs in vitro [10]. Intra-articular resveratrol treatment reduced cartilage loss in rabbit arthritis models. Resveratrol induced fi broblast apoptosis but increased chondrocyte survival by activating Sirtuin 1 (a histone deacetylase) and Bcl2 [11,12]. Th us, resveratrol may prevent intervertebral disc degeneration, OA-associated infl ammation, chondrocyte apoptosis, and RA-related pannus formation, desirable goals in treating OA and RA. Resveratrol-like Sirtuin 1 activators are also being developed as lifespan-extending drugs.
It is laudable that regulatory agencies are encouraging research to substantiate the therapeutic claims by manufacturers of NHPs. We need well-controlled, molecular and mechanistic studies on NHPs as modeled by Haqqi and colleagues [1]. Currently, we can analyze multiple targets of NHPs by gene arrays and proteomics to evaluate their effi cacy in preventing and treating RA and OA.

Competing interests
The authors declare that they have no competing interests.