A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype

Objectives The aim of this study was to assess if genetic variation in the PACE4 (paired amino acid converting enzyme 4) gene Pcsk6 influences the risk for symptomatic knee osteoarthritis (OA). Methods Ten PCSK6 single nucleotide polymorphisms were tested for association in a discovery cohort of radiographic knee OA (n=156 asymptomatic and 600 symptomatic cases). Meta-analysis of the minor allele at rs900414 was performed in three additional independent cohorts (total n=674 asymptomatic and 2068 symptomatic). Pcsk6 knockout mice and wild-type C57BL/6 mice were compared in a battery of algesiometric assays, including hypersensitivity in response to intraplantar substance P, pain behaviours in response to intrathecal substance P and pain behaviour in the abdominal constriction test. Results In the discovery cohort of radiographic knee OA, an intronic single nucleotide polymorphism at rs900414 was significantly associated with symptomatic OA. Replication in three additional cohorts confirmed that the minor allele at rs900414 was consistently increased among asymptomatic compared to symptomatic radiographic knee OA cases in all four cohorts. A fixed-effects meta-analysis yielded an OR=1.35 (95% CI 1.17 to 1.56; p=4.3×10−5 and no significant between-study heterogeneity). Studies in mice revealed that Pcsk6 knockout mice were significantly protected against pain in a battery of algesiometric assays. Conclusions These results suggest that a variant in PCSK6 is strongly associated with protection against pain in knee OA, offering some insight as to why, in the presence of the same structural damage, some individuals develop chronic pain and others are protected. Studies in Pcsk6 null mutant mice further implicate PACE4 in pain

Proliferative diabetic retinopathy in long-term diabetic patients with and without clinical osteoarthritis

Objective To determine whether some long-term diabetic patients with coexisting clinical osteoarthritis (OA) are less likely to develop diabetic retinopathy (DR) than other diabetic patients and whether there is a relation between the timing of the clinical OA onset and DR.Design, setting, and participantsRetrospective case-control study of 85 osteoarthritic patients with 20 years or more diabetes (A/DM) control group and of 85 non-osteoarthritic diabetic patients (NoA/DM) matched for age, race, duration, and type of diabetes. Digital fundus photographs were graded for retinopathy in masked manner. Results Glycosylated hemoglobin, hypertension, and smoking showed no significant difference. Twelve out of 85 patients (12.9%) in A/DM group developed proliferative diabetic retinopathy (PDR) whereas 79/85 (92.9%) NoA/DM patients developed PDR (P<0.001). The onset of OA symptoms was known in 80/85 of the A/D patients, including 47 patients with onset before or at the same year as DM and 33 patients with relative onset after the year of DM. All the 10 patients with PDR (10/33) developed OA subsequent to their initiation for diabetic treatment while 0/47 A/DM patients with the onset of osteoarthritic symptoms present before or the same year as their onset of diabetes developed PDR (P<0.001). Conclusion Our study suggests that in long-term DM, PDR was significantly associated with the absence of concomitant clinical OA. This observation was highly significant if the onset of the arthritis was the same year or before the onset of the diabetes. © 2013 Macmillan Publishers Limited. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe