A compelling genetic association with osteoarthritis (OA) of a functional SNP (rs143383, T/C) in the 5'-UTR of the GDF5 gene was recently reported in case-control cohorts from Japan and China. GDF5 is a pro-chondrogenic growth factor. The T-allele frequency of the gene was elevated in cases, with an odds ratio (OR) of 1.79, and in vitro functional studies demonstrated that this allele mediated a moderate but significant reduction in the activity of the GDF5 promoter in several cell lines. Our initial objective was to assess whether the SNP was also associated with OA in a broad European population by genotyping the SNP in 2487 cases and 2018 age-matched controls from the UK and Spain. The T-allele was associated with OA (P = 0.03, OR = 1.10) as was carrier status for this allele (P = 0.004, OR = 1.28), demonstrating that the SNP is associated with OA in two diverse ethnic groups, Asians and Europeans. We subsequently assessed the functional effect of the SNP on GDF5 allelic expression using RNA extracted from the cartilage of OA patients who had undergone joint-replacement surgery. The associated T-allele showed up to a 27% reduction in expression relative to the C-allele (P = 0.00007), revealing that the functional effect mediated by SNP rs143383 on GDF5 expression is active in patients who have severe disease up to the point at which they require surgery. A small but persistent imbalance of GDF5 expression throughout life therefore appears to render an individual more susceptible to OA.

Objective. Single-nucleotide polymorphism (SNP) rs143383 (T to C) in the 5 -untranslated region (5 -UTR) of GDF5 has recently been reported to be associated with osteoarthritis (OA) susceptibility, with lower expression of the risk-associated T allele observed in vitro and in vivo. The in vivo studies were performed on cartilage tissue from OA patients. The present study was undertaken to expand the analysis of the effect of this SNP on GDF5 allelic expression to more joint tissue types, to investigate for cis and trans factors that interact with the SNP, and to examine novel cis-acting GDF5 regulatory polymorphisms.Methods. Tissue samples were collected from OA patients undergoing joint replacement of the hip or knee. Nucleic acid was extracted, and, using rs143383 and an assay that discriminates and quantifies allelic expression, the relative amount of GDF5 expression from the T and C alleles was measured. Additional common variants in the GDF5 transcript sequence were interrogated as potential regulatory elements using allelic expression and luciferase reporter assays, and electrophoretic mobility shift assays were used to search for trans factors binding to rs143383.Results. We observed a consistent allelic expression imbalance of GDF5 in all tissues tested, implying that the functional effect mediated by rs143383 on GDF5 expression is joint-wide. We identified a second polymorphism, located in the 3 -UTR of GDF5, that influenced allelic expression of the gene independent of rs143383. Finally, we observed differential binding of deformed epidermal autoregulatory factor 1 (DEAF-1) to the 2 alleles of rs143383.Conclusion. These findings show that the OA susceptibility mediated by polymorphism in GDF5 is not restricted to cartilage, emphasizing the need to consider the disease as involving the whole joint. The existence of an additional cis-acting regulatory polymorphism highlights the complexity of the regulation of expression of this important OA susceptibility locus. DEAF-1 is a trans-acting factor that merits further investigation as a potential tool for modulating GDF5 expression.

Background: Assessment of gene expression is an important component of osteoarthritis (OA) research, greatly improved by the development of quantitative real-time PCR (qPCR). This technique requires normalization for precise results, yet no suitable reference genes have been identified in human articular cartilage. We have examined ten well-known reference genes to determine the most adequate for this application.

Our findings implicate ADAMTS14 in OA, specifically in knee OA requiring joint replacement in women and, possibly, in hand OA. Independent association of ADAMTS14 genetic variation to knee OA in women has been communicated. ADAMTS14 involvement, if confirmed, will open a new area of interest in OA pathogenesis because of its role in the maturation of collagen fibers.

& AbstractObjective: To evaluate tolerability, safety, and quality-oflife outcomes in non-opioid-pretreated patients with severe chronic low back pain with a neuropathic component receiving tapentadol PR vs. oxycodone/naloxone PR. Methods: Eligible patients (average pain intensity [numerical rating scale] ≥ 6; painDETECT positive/unclear ratings) were randomized to twice-daily tapentadol PR 50 mg or oxycodone/naloxone PR 10 mg/5 mg. After a 21-day titration (maximum twice-daily doses: tapentadol PR 250 mg, or oxycodone/naloxone PR 40 mg/20 mg plus oxycodone PR 10 mg), target doses were continued for 9 weeks. Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) total score from baseline to final evaluation was a primary endpoint. Results: For the primary tolerability-related endpoint, the 97.5% exact repeated confidence interval for tapentadol PR minus oxycodone/naloxone PR for the PAC-SYM total score was [À0.259, 0.121], showing noninferiority (upper limit < 0.7). Incidences of constipation and vomiting were significantly lower with tapentadol PR than oxycodone/naloxone PR (P ≤ 0.045). Confirmatory superiority based on formal noninferiority was shown for the primary effectiveness endpoint (change from baseline to final evaluation in pain intensity) for tapentadol PR vs. oxycodone/naloxone PR (presented separately). Improvements in the Short Form-12 physical component summary and EuroQol-5 Dimension health status index and health state assessment were