Abstract
ObjectiveSulforaphane (SFN) has been reported to regulate signaling pathways relevant to chronic diseases. The aim of this study was to investigate the impact of SFN treatment on signaling pathways in chondrocytes and to determine whether sulforaphane could block cartilage destruction in osteoarthritis.MethodsGene expression, histone acetylation, and signaling of the transcription factors NF-E2–related factor 2 (Nrf2) and NF-κB were examined in vitro. The bovine nasal cartilage explant model and the destabilization of the medial meniscus (DMM) model of osteoarthritis in the mouse were used to assess chondroprotection at the tissue and whole-animal levels.ResultsSFN inhibited cytokine-induced metalloproteinase expression in primary human articular chondrocytes and in fibroblast-like synovial cells. SFN acted independently of Nrf2 and histone deacetylase activity to regulate metalloproteinase expression in human articular chondrocytes but did mediate prolonged activation of JNK and p38 MAPK. SFN attenuated NF-κB signaling at least through inhibition of DNA binding in human articular chondrocytes, with decreased expression of several NF-κB–dependent genes. Compared with cytokines alone, SFN (10 μM) abrogated cytokine-induced destruction of bovine nasal cartilage at both the proteoglycan and collagen breakdown levels. An SFN-rich diet (3 μmoles/day SFN versus control chow) decreased the arthritis score in the DMM model of osteoarthritis in the mouse, with a concurrent block of early DMM-induced gene expression changes.ConclusionSFN 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.
Highlights
Gene expression, histone acetylation, and signaling of the transcription factors NF-E2– related factor 2 (Nrf2) and NF-B were examined in vitro
SFN inhibits the expression of key metalloproteinases implicated in osteoarthritis, independently of Nrf2, and blocks inflammation at the level of NF-B to protect against cartilage destruction in vitro and in vivo
Two key molecules that endow cartilage extracellular matrix with its structural properties are type II collagen and the proteoglycan aggrecan. The former molecule is principally turned over by the action of collagenolytic matrix metalloproteinases (MMPs; e.g., MMP-1 and MMP-13), while enzymes from the ADAMTS family are responsible for metabolism of the latter molecule [1]
Summary
Histone acetylation, and signaling of the transcription factors NF-E2– related factor 2 (Nrf2) and NF-B were examined in vitro. SFN and its metabolites were obtained from Toronto Research Chemicals, except SFN–Cys-Gly, which was synthesized by Dr Sunil Sharma, University of East Anglia. Sc-372), p50, and c-Rel primary antibodies were obtained from Santa Cruz Biotechnology. Small interfering RNA (siRNA) against Nrf (Ambion) and AllStars nontargeting siRNA were from Qiagen; staurosporine was obtained from Sigma-Aldrich; and trichostatin A and sodium butyrate were from Calbiochem.
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