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ObjectiveTo assess if a coding variant in the gene encoding transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is associated with genetic risk of painful knee osteoarthritis (OA).MethodsThe Ile585Val TRPV1 variant encoded by rs8065080 was genotyped in 3270 cases of symptomatic knee OA, 1098 cases of asymptomatic knee OA and 3852 controls from seven cohorts from the UK, the USA and Australia. The genetic association between the low-pain genotype Ile–Ile and risk of symptomatic and asymptomatic knee OA was assessed.ResultsThe TRPV1 585 Ile–Ile genotype, reported to be associated with lower thermal pain sensitivity, was associated with a lower risk of symptomatic knee OA in a comparison of symptomatic cases with healthy controls, with an odds ratio (OR) of 0.75 (95% CI 0.64 to 0.88; p=0.00039 by meta-analysis) after adjustment for age, sex and body mass index. No difference was seen between asymptomatic OA cases and controls (OR=1.02, 95% CI 0.82 to 1.27 p=0.86) but the Ile–Ile genotype was associated with lower risk of symptomatic versus asymptomatic knee OA adjusting for covariates and radiographic severity (OR=0.73, 95% CI 0.57 to 0.94 p=0.0136). TRPV1 expression in articular cartilage was increased by inflammatory cytokines (tumour necrosis factor α and interleukin 1). However, there were no differences in TRPV1 expression in healthy and arthritic synovial tissue.ConclusionsA genotype involved in lower peripheral pain sensitivity is significantly associated with a decreased risk of painful knee OA. This indicates a role for the pro-nociceptive gene TRPV1 in genetic susceptibility to symptomatic knee OA, which may also be influenced by a role for this molecule in cartilage function.

The deletion of phenylalanine at position 508 (F508del) in cystic fibrosis transmembrane conductance regulator (CFTR) causes a severe defect in folding and trafficking of the chloride channel resulting in its absence at the plasma membrane of epithelial cells leading to cystic fibrosis. Progress in the understanding of the disease increased over the past decades and led to the awareness that combinations of mechanistically different CFTR modulators are required to obtain meaningful clinical benefit. Today, there remains an unmet need for identification and development of more effective CFTR modulator combinations to improve existing therapies for patients carrying the F508del mutation. Here, we describe the identification of a novel F508del corrector using functional assays. We provide experimental evidence that the clinical candidate GLPG/ABBV-2737 represents a novel class of corrector exerting activity both on its own and in combination with VX809 or GLPG/ABBV-2222.

Tumor necrosis factor (TNF)1 can induce cell death by necrosis or apoptosis, depending on the cell line (1-4) and/or the intracellular ATP concentration (5). Apoptosis is morphologically characterized by membrane blebbing, shrinking of the cell and its organelles, and internucleosomal degradation of DNA (6). Finally, the cell disintegrates and apoptotic bodies are cleared by phagocytosis, in most cases without any detrimental effects on the surrounding tissue (7,8). In contrast, cell death by necrosis is often accompanied by inflammation due to massive release of the cytoplasmic cell content. Necrosis is characterized by swelling of the cell and its organelles and an immediate loss of the plasma membrane integrity (1). A key step in the pathway to apoptosis is activation of procaspases. Activation of these cysteinyl aspartate-specific proteases is initiated by formation of a death-inducing signaling complex (DISC) after oligomerization of the p55 TNF receptor (TNF-R55) or the Fas receptor by the respective ligands (9, 10). Both death receptors contain a homologous C-terminal cytoplasmic death domain (DD) involved in apoptosis (11,12). After binding of TNF to TNF-R55, the clustered DDs recruit the TNF-R55-associated DD-containing protein TRADD (13-15). TRADD in turn recruits Fas-associated DD protein (FADD) by DD-DD interaction (13). In contrast, the DD of Fas does not require the TRADD adaptor protein but serves as a direct docking surface for FADD (16 -18). Besides its C-terminal DD, FADD contains a death effector domain (DED) implicated in the recruitment of procaspase-8 (19, 20). Oligomerization of procaspase-8 leads to proximity-induced autocatalytic activation followed by direct or indirect downstream activation of executionary caspases, which cleave substrates involved in apoptotic morphology (21,22).The initial intracellular molecular events responsible for necrosis are less well understood. Leist and co-workers (5) proposed a model in which low cellular ATP concentrations give rise to a necrotic cell death process, whereas in the presence of high ATP concentrations the apoptotic, caspase-dependent pathway becomes apparent. On the other hand, it was shown that mitochondria are crucial in the necrotic process (reviewed in Ref. 4). Depletion of mitochondria protects L929sA cells from necrotic cell death (23), and TNF induces the production of mitochondrial reactive oxygen intermediates (ROI) (24). This oxidative phosphorylation-linked ROI production is required for TNF-induced necrotic cell death, since addition of butylated hydroxyanisole (BHA), an oxygen radical scavenger and inhibitor of oxidative phosphorylation (25), blocks TNF cytotoxicity (24). Recently, we demonstrated that inhibition of caspase ac-* This work was supported in part by the Interuniversitaire Attractiepolen. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.‡ T...