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

TY - JOUR

T1 - A role for PACE4 in osteoarthritis pain

T2 - evidence from human genetic association and null mutant phenotype

AU - Malfait, Anne-Marie

AU - Seymour, Albert B.

AU - Gao, Feng

AU - Tortorella, Micky D.

AU - Le Graverand-Gastineau, Marie-Pierre Hellio

AU - Wood, Linda S.

AU - Doherty, Michael

AU - Doherty, Sally

AU - Zhang, Weiya

AU - Arden, Nigel K.

AU - Vaughn, Frances L.

AU - Leaverton, Paul E.

AU - Spector, Tim D.

AU - Hart, Deborah J.

AU - Maciewicz, Rose A.

AU - Muir, Kenneth R.

AU - Das, Rosalina

AU - Sorge, Robert E.

AU - Sotocinal, Susanna G.

AU - Schorscher-Petcu, Ara

AU - Valdes, Ana M.

AU - Mogil, Jeffrey S.

PY - 2012/6

Y1 - 2012/6

N2 - 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=4.3x10(-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.

AB - 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=4.3x10(-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.

KW - RADIOGRAPHIC KNEE OSTEOARTHRITIS

KW - O-METHYLTRANSFERASE GENE

KW - MOUSE STRAINS

KW - UNITED-STATES

KW - POLYMORPHISM

KW - CONVERTASES

KW - ACTIVATION

KW - SYMPTOMS

KW - PROTEASE

KW - MICE

U2 - 10.1136/annrheumdis-2011-200300

DO - 10.1136/annrheumdis-2011-200300

M3 - Article

SN - 0003-4967

VL - 71

SP - 1042

EP - 1048

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 6

M1 - N/A

ER -