Isothiocyanates are detected in human synovial fluid following broccoli consumption and can affect the tissues of the knee joint

Abstract

Osteoarthritis is a major cause of disability and there is no current pharmaceutical treatment which can prevent the disease or slow its progression. Dietary advice or supplementation is clearly an attractive option since it has low toxicity and ease of implementation on a population level. We have previously demonstrated that sulforaphane, a dietary isothiocyanate derived from its glucosinolate precursor which is found in broccoli, can prevent cartilage destruction in cells, in in vitro and in vivo models of osteoarthritis. As the next phase of this research, we enrolled 40 patients with knee osteoarthritis undergoing total knee replacement into a proof-of-principle trial. Patients were randomised to either a low or high glucosinolate diet for 14 days prior to surgery. We detected ITCs in the synovial fluid of the high glucosinolate group, but not the low glucosinolate group. This was mirrored by an increase in ITCs and specifically sulforaphane in the plasma. Proteomic analysis of synovial fluid showed significantly distinct profiles between groups with 125 differentially expressed proteins. The functional consequence of this diet will now be tested in a clinical trial.Osteoarthritis (OA) of the hip or knee is ranked as 11 th of 291 conditions that contribute to global disability; and the consequent years lived with disability (YLDs) are estimated to have risen by 61% from 1990-2010 1 . There are no disease-modifying OA drugs (DMOADs) currently available, and pharmacological interventions provide symptomatic relief only, which is frequently insufficient 2, 3 .The National Institute for Health and Care Excellence (NICE) and the American College of Rheumatology both recommend OA management strategies based upon activity and exercise, and weight loss if overweight or obese. A third core treatment area recommended by NICE focuses on information to support self-management 4, 5 . Within these core treatment areas, dietary and exercise advice have been identified as cost effective approaches to the treatment of OA 6 .We and others have shown previously that sulforaphane (1-isothiocyanato-4-methylsulfinylbutane, SFN) is a chondroprotective agent in vitro and in vivo [7][8][9][10] . SFN is derived from a precursor, glucoraphanin, gained from eating brassicas, particularly broccoli. Sulforaphane has broad biological activity and its role in joint health was recently reviewed 11 . SFN can repress the expression of key metalloproteinases implicated in OA 7, 10 , regulate NF-κB and Nrf2 signalling, inhibit production of prostaglandin E2 and nitric oxide in chondrocytes 7, 9, 10 and prevent cytokine-induced cartilage destruction in vitro 9,10 . In vivo, SFN reduces cartilage destruction in the 'destabilisation of the medial meniscus' (DMM) murine model of OA 10 and inhibits synovial hyperplasia in collagen-induced arthritis (CIA) 8 . Nrf2 knockout mice also showed increased cartilage lesions and oxidative damage in antibody-induced arthritis (AIA) 12 .The pharmacokinetics of SFN has been studied, with one report measuring t...

Glycation marker glucosepane increases with the progression of osteoarthritis and correlates with morphological and functional changes of cartilage in vivo

“…With the emergence of serum GSP free adduct as a potential marker of OA from the guinea pig study and chondrocyte studies, we analyzed serum GSP in patients and healthy controls, including a study group with aOA, pre-TKR surgery. Clinical characteristics were presented previously [ 14 , 20 ]. Plasma GSP free adduct was increased 38% in eOA, sixfold in aOA, pre-TKR, twofold in non-RA, and threefold in eRA (Table 2 ).…”

“…Patient recruitment, characteristics, and sampling were similar to those previously described [ 14 ]. Briefly, patients with early-stage OA (eOA) ( n = 28), early-stage rheumatoid arthritis (eRA) ( n = 35), and inflammatory joint disease other than rheumatoid arthritis (often self-resolving) (non-RA) ( n = 32) were recruited.…”

“…Recruitment of patients with advanced OA ( n = 38) immediately prior to total knee replacement (TKR) surgery (advanced osteoarthritis [aOA], pre-TKR) was done with written informed consent from patients referred for TKR to the Norfolk and Norwich University Hospitals NHS Trust (NNUH), Norwich, UK. Patients were screened for study eligibility criteria as described previously [ 14 ]. Eligible patients were males or postmenopausal females scheduled for TKR.…”

The Role of MicroRNAs in the Chemopreventive Activity of Sulforaphane from Cruciferous Vegetables

“…Isothiocyanates are to date the most-studied and best-characterised of known glucosinolate-hydrolysis-derived products in terms of their bioactivity. They are believed to play a defensive role in the plants via their cytotoxic effects on microorganisms and small parasitic animals, but to be directly beneficial to human health via broad anti-inflammatory and antioxidant effects, and thus are able to help inhibit the development of cancers [ 12 ], cardiovascular diseases [ 13 ], and osteoarthritis [ 14 , 15 ]. Broccoli is particularly high in a particular glucosinolate called glucoraphanin, whose myrosinase-mediated hydrolysis generates an isothiocyanate called sulforaphane (SFN, 1-isothiocyanato-4-(methylsulfinyl)butane), the structure of which is depicted in Figure 1 .…”

Influência do sulforafano, um inibidor de histonas desacetilases, sobre a instabilidade genômica e mecanismos epigenéticos em linhagens celulares humanas

“…Um estudo sobre a farmacocinética do sulforafano demonstrou que o pico da concentração plasmática de sulforafano foi de aproximadamente 2,2 µM após 2 horas do consumo de 100g de brócolis preparado como uma sopa(GASPER et al, 2005). Não há evidências de que a ingestão dietética normal de brócolis esteja associada à toxicidade, mesmo a longo prazo(DAVIDSON et al, 2017). vias moleculares são capazes de proteger células e organismos contra carcinogênese, mutagênese e outras formas de toxicidade (YANG; PALLIYAGURU; KENSLER, 2016).…”