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Objectives: To determine cross-sectionally the influence of risk factors on chronic pain following total joint replacement (TJR) of the knee (TKR) or the hip (THR). Methods: Eight hundred sixty post-TKR and 928 post-THR patients were studied. Western Ontario and McMaster Osteoarthritis Index pain scores taken on average 3.2 years postsurgery were correlated to preoperative radiographic severity measured by Kellgren-Lawrence grade (K/L) grade for the knee, Croft grade, and minimum joint space width (minJSW) for the hip and presence of comorbidities. Results: Known risk factors were able to explain less than 20% of the variance in pain scores post-TJR. The presence of chronic widespread pain determined a higher risk of high pain in both TKR cases (odds ratio (OR) = 3.15 95%CI 1.86-5.30) and THR cases (OR = 5.02 95%CI 2.76-9.14). Other risk factors common to both TKR and THR pain postsurgery were the presence of depression, higher body mass index, younger age, and female gender. Interestingly, low radiographic grade at the index joint presurgery (defined as tibiofemoral K/L <3 for the knee and minJSW >2 mm for the hip) resulted in a significantly increased risk of high pain post-TJR (OR = 1.56; 95%CI 1.04-2.36). Conclusions: The risk factors contributing to chronic pain post-TJR remain mostly unknown. Individuals with lower preoperative radiographic OA severity undergoing TJR are more likely to experience high pain post-TJR. [Copyright &y& Elsevier]

Abstract: Piperidine ether and aryl piperazine hydantoins are reported as potent inhibitors of MMP13. A medicinal chemistry campaign focused on replacing the reverse hydroxamate zinc binding group associated with historical inhibitors with a hydantoin zinc binding group then optimising MMP13 potency, solubility and DMPK properties whilst maintaining good selectivity over MMP14. A number of high quality candidates were progressed and following rat and dog safety evaluation, AZD6605 (3m) was identified as a candidate drug. [Copyright &y& Elsevier]

Tumor necrosis factor (TNF) α-converting enzyme (TACE/ADAM-17) has diverse roles in the proteolytic processing of cell surface molecules and, due to its ability to process TNFα is a validated therapeutic target for anti-inflammatory therapies. Unlike a number of other ADAM proteins, which interact with integrin receptors via their disintegrin domains, there is currently no evidence for an ADAM-17-integrin association. By analyzing the adhesion of a series of cell lines with recombinant fragments of the extracellular domain of ADAM-17, we now demonstrate a functional interaction between ADAM-17 and α5β3 integrin in a trans orientation. Because ADAM-17-mediated adhesion was sensitive to RGD peptides and EDTA, and the integrin-binding site within ADAM-17 was narrowed down to the disintegrin/ cysteine-rich region, the two molecules appear to have a ligand-receptor relationship mediated by the α5β1 ligand binding pocket. Intriguingly, ADAM-17 and α5β1 were found to co-localize in both membrane ruffles and focal adhesions in HeLa cells. When confluent HeLa cell monolayers were wounded, ADAM-17 and α5β1 redistributed to the leading edge and co-localized, which is suggestive of a cis orientation. We postulate that the interaction of ADAM-17 with α5β1 may target or modulate its metalloproteolytic activity. [ABSTRACT FROM AUTHOR]