Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
A Role for PACE4 in Pain in Mice and Humans: Pain Phenotype of a PACE4 Null Mutant and Genetic Association with Knee Osteoarthritis Pain.
Malfait6, Anne-Marie M., Seymour5, Albert B., Valdes4, Ana M., Wood5, Linda S., Durham5, Kathryn, Tortorella3, Micky, Arden8, Nigel K.
Dept of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada
Dept of Psychology and Alan Edwards Centre for Research on Pain, McGill University
Guangzhou Institute of Biomedical Health, Guangzhou, China
King's College London, London, United Kingdom
Pfizer Global Research and Development, Cambridge, MA
Rush University Medical Center, Chicago, IL
The Arthritis Research Institute of America, Clearwater, FL
University of Oxford, Oxford, United Kingdom
PACE4 is a member of the proprotein convertase family of serine proteases essential for the proteolytic maturation of a wide variety of proteins, including growth factors, hormones, and zymogens. We recently reported that PACE4 activates the aggrecanases, ADAMTS-4 and ADAMTS-5, in human osteoarthritic (OA) cartilage. The aim of the current study was to assess if genetic variants in the PACE4 gene are implicated in the risk for knee OA.
Methods and Subjects:
The rs900414 single nucleotide polymorphism (SNP) in the PACE4 gene (PCSK6) was genotyped in three independent cohorts ("Discovery": 508 symptomatic knee OA cases, 159 asymptomatic knee OA, and 276 controls; "Clearwater": 85 symptomatic and 92 asymptomatic knee OA cases; and "Chingford" 62 symptomatic, 157 asymptomatic knee OA cases, and 527 controls). In follow-up to the human findings, PACE4 KO mice and wildtype littermates (C57BL/6) were tested on a battery of algesiometric assays, including mechanical and thermal hypersensitivity in response to intraplantar administration of substance P (SP) (2.520 mg), and for pain behavior in response to intrathecal SP (545 ng) or in response to intraperitoneal injection of 0.6% acetic acid.
The minor allele at rs900414 (allele frequency 32%) was found to be significantly associated with symptomatic OA in the discovery samples and to be consistently increased among asymptomatic OA cases compared to symptomatic knee OA in all three cohorts. A fixed-effects meta-analysis yielded OR=1.34 (95% CI 1.09 1.64) p=0.005 (Figure 1) and no between-study hetereogeneity was observed (I2=0%). PACE4 KO mice displayed normal baseline sensitivity to thermal and mechanical stimuli as assessed by paw withdrawal, von Frey, tail-clip, hot-plate and tail-withdrawal tests. However, PACE4 KO mice developed significantly less thermal and mechanical hypersensitivity in response to intraplantar injection of SP. In addition, intrathecal injection of substance P resulted in a dose-dependent induction of pain behaviors (scratching, biting and licking) in wildtype but not in PACE4 KO mice. Moreover, compared to wildtypes, PACE4 KO mice showed >50% less pain behavior in the acetic acid writhing test.
These results suggest that the rs900414 SNP in the human PACE4 gene is strongly associated with protection against pain in knee OA. Studies in PACE4 KO mice further implicate PACE4 in pain.
Figure 1. Forest plot showing study specific effect size estimates and summary odds ratio for the association between the PACE4 SNP rs900414 and risk of asymptomatic OA vs symptomatic OA.
To cite this abstract, please use the following information:
Malfait, Anne-Marie M., Seymour, Albert B., Valdes, Ana M., Wood, Linda S., Durham, Kathryn, Tortorella, Micky, et al; A Role for PACE4 in Pain in Mice and Humans: Pain Phenotype of a PACE4 Null Mutant and Genetic Association with Knee Osteoarthritis Pain. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :823