Abstract
Purpose: Nutrition impacts directly on ageing and obesity, both of which are major risk factors for osteoarthritis. Sulforaphane (SFN) is an isothiocyanate derived from brassicas, particularly broccoli, and has been reported to regulate signalling pathways relevant to chronic diseases. Our study investigated whether sulforaphane can abrogate cartilage destruction in laboratory models of osteoarthritis and examined mechanism of action in chondrocytes. Methods: The impact of SFN treatment on gene expression, signalling through transcription factors nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and nuclear factor kappaB (NFκB), and histone acetylation were examined in chondrocytes. The intracellular concentrations of SFN and SFN metabolites were quantified in chondrocytes and used to inform transcription factor binding assays. The bovine nasal cartilage explant model (BNC) and destabilisation of medial meniscus (DMM) murine model of osteoarthritis were used to study chondroprotection by SFN. Results: SFN inhibited cytokine-induced metalloproteinase expression in primary human articular chondrocytes (HACs) and in fibroblast-like synovial cells (FLS). SFN can act independently of the Nrf2 transcription factor and histone deacetylase activity in HACs, but does mediate prolonged activation of Jun kinase (JNK) and p38 MAP kinase. SFN attenuates NF-κB signalling through at least inhibition of DNA binding in HACs with attenuation of expression of several NF-κB dependent genes. SFN abrogates cytokine-induced destruction of bovine nasal cartilage at the level of both proteoglycan and collagen breakdown (10μM compared to cytokines alone). It also decreases arthritis score in the DMM murine model of osteoarthritis (3μmol daily dose SFN in diet versus control chow). Conclusions: SFN, at levels which can be obtained through a broccoli-rich diet, inhibits the expression of key metalloproteinases implicated in osteoarthritis independently of Nrf2 and blocks inflammation at the level of NF-κB to protect against cartilage destruction in vitro and in vivo. Ongoing studies in man will ascertain the potential of this compound in human osteoarthritis.
Highlights
There is currently no cure for osteoarthritis (OA), or therapies which slow or arrest OA progression
SFN, at levels which can be obtained through a broccolirich diet, inhibits the expression of key metalloproteinases implicated in osteoarthritis independently of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and blocks inflammation at the level of NF-kB to protect against cartilage destruction in vitro and in vivo
The lead compounds from these screens were assayed in three isolates of primary human articular chondrocytes for their impact on expression of MMP13, MMP1, ADAMTS4 and ADAMTS5
Summary
There is currently no cure for osteoarthritis (OA), or therapies which slow or arrest OA progression. Results: SFN inhibited cytokine-induced metalloproteinase expression in primary human articular chondrocytes (HACs) and in fibroblast-like synovial cells (FLS). SFN abrogates cytokine-induced destruction of bovine nasal cartilage at the level of both proteoglycan and collagen breakdown (10mM compared to cytokines alone) It decreases arthritis score in the DMM murine model of osteoarthritis (3mmol daily dose SFN in diet versus control chow). Conclusions: SFN, at levels which can be obtained through a broccolirich diet, inhibits the expression of key metalloproteinases implicated in osteoarthritis independently of Nrf and blocks inflammation at the level of NF-kB to protect against cartilage destruction in vitro and in vivo. Current pharmacological intervention for osteoarthritis (OA) is focused on inflammation and pain relief rather than addressing the degradation of articular cartilage Such treatments typically have a single mode of action in a multifactorial disease. Compound toxicity was measured using lactate dehydrogenase release and FACS
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