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Figure S1. MEK inhibitor works to reduce pERK1/2 and enhances IFN-β release. Figure S2. Challenge with poly(I:C) is similar but not identical to challenge with RV2. Figure S3. PI3Ki does not cause cytotoxicity. Figure S4. Enhanced IFN-β response due to MEKi is not associated with increased IRF7 protein expression. Figure S5. Challenge with poly(I:C) is similar but not identical to challenge with RV2 or RSVA2. Figure S6. Induction of ISG15 mRNA by poly(I:C) is similar to that of RV2. Figure S7. MEKi reduces phosphorylation of STAT3 at S727. Table S1. NHBE donors. Table S2. Structure of small molecules and PROTACs. Table S3. List of antibodies used for immunoblotting. Table S4. Target sequence of short interfering RNA (siRNA). Table S5. List of Taqman primer/probe. (DOCX 1110 kb)

Objective: Recent findings suggest that β-adrenergic blockers have anti-nociceptive properties. The aim of this study was to compare levels of large joint pain between those on adrenergic blockers and those on other antihypertensive medications. Methods: Data from the GOAL study, a secondary care cohort of osteoarthritis (OA), were used. Joint pain was assessed using the Western Ontario and McMaster Universities Arthritis (WOMAC) pain score in 873 individuals who had symptomatic hip and/or knee OA and hypertension, and who were on ≥1 prescription antihypertensive medications. The association between adrenergic blocker prescription and a) at least moderate joint pain (WOMAC

Introduction: The objective was to investigate potential gene-environment interaction between body mass index (BMI) and each of eight TGF?1 polymorphisms in knee and hip osteoarthritis (OA).Methods: We conducted a case-control study of Caucasian men and women aged 45 to 86 years from Nottingham, United Kingdom (Genetics of OA and Lifestyle (GOAL) study). Cases had clinically severe symptoms and radiographic knee or hip OA; controls had no symptoms and no radiographic knee/hip OA. We used logistic regression to investigate the association of TGF?1 polymorphisms and OA when stratifying by BMI. Knee and hip OA were analyzed separately with adjustment for potential confounders. Additive and multiplicative interactions were examined.Results: 2,048 cases (1,042 knee OA, 1,006 hip OA) and 967 controls were studied. For hip OA, the highest risk was in overweight (BMI ?25 kg/m2) individuals with the variant allele of single-nucleotide polymorphism (SNP)rs1800468 (odds ratio (OR) 2.21, 95% confidence interval (CI) 1.55, 3.15). Evaluation of gene-environment interaction indicated significant synergetic interaction (relative excess risk due to interaction (RERI) = 0.93, synergy index (SI) = 4.33) with an attributable proportion due to interaction (AP) of 42% (AP = 0.42; 95% CI 0.16, 0.68). Multiplicative interaction was also significant (OR for interaction (ORINT) = 2.27, P = 0.015). For knee OA, the highest risk was in overweight individuals with homozygous genotype 11 of SNP rs2278422 (OR = 6.95, P < 0.001). In contrast, the variant allele indicated slightly lower risks (OR = 4.72, P < 0.001), a significant antagonistic interaction (RERI = -2.66, SI = 0.59), AP = -0.56 (95%CI -0.94, -0.17) and a significant multiplicative interaction (ORINT = 0.47, P = 0.013).Conclusion: TGF?1 gene polymorphisms interact with being overweight to influence the risk of large joint OA.

The role of cathepsin L in normal physiological processes was assessed using cathepsin L homozygous knockout mice (B6;129-Ctsl(tm1Alpk)). These mice were generated using gene targeting in embryonic stem cells. Null mice fail to express mRNA and protein to cathepsin L. They developed normally and were fertile. The distinct phenotypic change exhibited was a progressive hair loss, culminating in extensive alopecia by 9 months of age. Histological analysis of the skin from homozygous mice revealed diffuse epithelial hyperplasia, hypotrichosis, hair shaft fragmentation and utricle formation. These findings provide evidence that cathepsin L is involved in the regulation of epithelial cell proliferation and differentiation in the skin. In addition, the role of cathepsin L in bone remodelling was evaluated. Using bone histomorphometric measurements, trabecular, but not cortical, bone volume was found to be significantly decreased in the cathepsin L heterozygote and homozygote mice compared to the wild-type mice. Following ovariectomy, it was observed that loss of trabecular bone, the most metabolically active component of bone, occurred to a lesser extent in homozygote, and heterozygote mice, than was seen in wild-type mice. These observations suggest that cathepsin L is likely to have a role in controlling bone turnover during normal development and in pathological states.

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10−8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.