Expression analysis of the osteoarthritis genetic susceptibility mapping to the matrix Gla protein gene MGP.
1-Carboxyglutamic Acid
Alleles
Calcium-Binding Proteins
/ biosynthesis
Chondrocytes
/ metabolism
Extracellular Matrix Proteins
/ biosynthesis
Gene Expression Regulation
Genetic Predisposition to Disease
Genome-Wide Association Study
/ methods
Genotype
Humans
Osteoarthritis
/ genetics
RNA
/ genetics
Matrix Gla Protein
Allelic expression
Genetic association signal
Knockdown
MGP
Osteoarthritis
RNA interference
Journal
Arthritis research & therapy
ISSN: 1478-6362
Titre abrégé: Arthritis Res Ther
Pays: England
ID NLM: 101154438
Informations de publication
Date de publication:
18 06 2019
18 06 2019
Historique:
received:
06
02
2019
accepted:
06
06
2019
entrez:
20
6
2019
pubmed:
20
6
2019
medline:
30
5
2020
Statut:
epublish
Résumé
Osteoarthritis (OA) is a common disease of older individuals that impacts detrimentally on the quality and the length of life. It is characterised by the painful loss of articular cartilage and is polygenic and multifactorial. Genome-wide association scans have highlighted over 90 osteoarthritis genetic signals, some of which reside within or close to highly plausible candidate genes. An example is an association to polymorphisms within and adjacent to the matrix Gla protein gene MGP. We set out to undertake a functional study of this gene. Nucleic acid was extracted from cartilage, infrapatellar fat pad, synovium, trabecular bone, trapezium and peripheral whole blood from OA patients and also from mesenchymal stem cells (MSCs) subjected to chondrogenesis. Expression of MGP was measured by quantitative PCR (qPCR), RNA-sequencing and allelic expression imbalance (AEI) analysis. Matrix Gla protein was depleted in chondrocytes by knocking down MGP expression using RNA interference (RNAi) and the effect on a range of genes assessed by qPCR. MGP is expressed in joint tissues, blood and chondrocytes cultured from MSCs. There is a higher expression in diseased versus non-diseased cartilage. Polymorphisms that are associated with OA also correlate with the expression of MGP, with the OA risk-conferring allele showing significantly reduced expression in cartilage, fat pad and synovium but increased expression in blood. Depletion of Matrix Gla protein had a significant effect on the majority of genes tested, with an increased expression of catabolic genes that encode enzymes that degrade cartilage. MGP expression is subject to cis-acting regulators that correlate with the OA association signal. These are active in a range of joint tissues but have effects which are particularly strong in cartilage. An opposite effect is observed in blood, highlighting the context-specific nature of the regulation of this gene's expression. Recapitulation of the genetic deficit in cartilage chondrocytes is pro-catabolic.
Sections du résumé
BACKGROUND
Osteoarthritis (OA) is a common disease of older individuals that impacts detrimentally on the quality and the length of life. It is characterised by the painful loss of articular cartilage and is polygenic and multifactorial. Genome-wide association scans have highlighted over 90 osteoarthritis genetic signals, some of which reside within or close to highly plausible candidate genes. An example is an association to polymorphisms within and adjacent to the matrix Gla protein gene MGP. We set out to undertake a functional study of this gene.
METHODS
Nucleic acid was extracted from cartilage, infrapatellar fat pad, synovium, trabecular bone, trapezium and peripheral whole blood from OA patients and also from mesenchymal stem cells (MSCs) subjected to chondrogenesis. Expression of MGP was measured by quantitative PCR (qPCR), RNA-sequencing and allelic expression imbalance (AEI) analysis. Matrix Gla protein was depleted in chondrocytes by knocking down MGP expression using RNA interference (RNAi) and the effect on a range of genes assessed by qPCR.
RESULTS
MGP is expressed in joint tissues, blood and chondrocytes cultured from MSCs. There is a higher expression in diseased versus non-diseased cartilage. Polymorphisms that are associated with OA also correlate with the expression of MGP, with the OA risk-conferring allele showing significantly reduced expression in cartilage, fat pad and synovium but increased expression in blood. Depletion of Matrix Gla protein had a significant effect on the majority of genes tested, with an increased expression of catabolic genes that encode enzymes that degrade cartilage.
CONCLUSIONS
MGP expression is subject to cis-acting regulators that correlate with the OA association signal. These are active in a range of joint tissues but have effects which are particularly strong in cartilage. An opposite effect is observed in blood, highlighting the context-specific nature of the regulation of this gene's expression. Recapitulation of the genetic deficit in cartilage chondrocytes is pro-catabolic.
Identifiants
pubmed: 31215457
doi: 10.1186/s13075-019-1934-7
pii: 10.1186/s13075-019-1934-7
pmc: PMC6582465
doi:
Substances chimiques
Calcium-Binding Proteins
0
Extracellular Matrix Proteins
0
1-Carboxyglutamic Acid
53445-96-8
RNA
63231-63-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
149Subventions
Organisme : Centre for Integrated Research into Musculoskeletal Ageing
ID : MR/R502182/1
Pays : International
Organisme : Versus Arthritis
ID : 20771
Pays : United Kingdom
Organisme : Centre for Integrated Research into Musculoskeletal Ageing
ID : JXR 10641
Pays : International
Organisme : FP7 Ideas: European Research Council
ID : 305815
Pays : International
Organisme : Arthritis Research UK
ID : 20771
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P020941/1
Pays : United Kingdom
Organisme : Centre for Integrated Research into Musculoskeletal Ageing
ID : MR/P020941/1
Pays : International
Références
BMC Med Genet. 2015 Nov 19;16:108
pubmed: 26584642
Semin Cell Dev Biol. 2017 Feb;62:57-66
pubmed: 27130636
Osteoarthritis Cartilage. 2017 Nov;25(11):1771-1780
pubmed: 28801210
Genome Biol. 2015 May 30;16:113
pubmed: 26025392
Genome Biol. 2014;15(12):550
pubmed: 25516281
Hum Mol Genet. 2007 Mar 1;16(5):537-46
pubmed: 17220169
FASEB J. 2012 Jul;26(7):3000-11
pubmed: 22505473
Tissue Eng Part A. 2017 Aug;23(15-16):738-749
pubmed: 28095751
Calcif Tissue Int. 2013 Oct;93(4):299-306
pubmed: 23183786
Arthritis Rheum. 2006 Apr;54(4):1255-61
pubmed: 16572460
Curr Med Chem. 2018 Jul 15;:
pubmed: 30009696
Development. 2017 Dec 15;144(24):4510-4521
pubmed: 29084806
Hum Mol Genet. 2018 Oct 1;27(19):3464-3474
pubmed: 30010910
J Rheumatol. 2011 Sep;38(9):1960-5
pubmed: 21724703
Nat Genet. 2017 May;49(5):801-805
pubmed: 28319091
Arthritis Rheumatol. 2015 Nov;67(11):2923-32
pubmed: 26211391
Osteoarthritis Cartilage. 2015 Mar;23(3):370-8
pubmed: 25528106
Dev Growth Differ. 2015 Feb;57(2):179-92
pubmed: 25714187
Nat Genet. 2018 Dec;50(12):1681-1687
pubmed: 30374069
Nature. 1997 Mar 6;386(6620):78-81
pubmed: 9052783
Arthritis Res Ther. 2017 Nov 10;19(1):248
pubmed: 29126436
Rheumatology (Oxford). 2018 May 1;57(suppl_4):iv61-iv74
pubmed: 29684218
J Cell Physiol. 2012 Apr;227(4):1298-308
pubmed: 21604271
Nat Genet. 2019 Feb;51(2):230-236
pubmed: 30664745
PLoS One. 2017 May 18;12(5):e0177829
pubmed: 28542410
Nat Genet. 2018 Apr;50(4):549-558
pubmed: 29559693
Ann Rheum Dis. 2017 Dec;76(12):2046-2053
pubmed: 28855172
Clujul Med. 2016;89(3):319-21
pubmed: 27547048
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
Arthritis Rheum. 2012 Jun;64(6):1697-707
pubmed: 22392533