Large-scale gene expression in bone marrow mesenchymal stem cells: a putative role for COL10A1 in osteoarthritis.
OBJECTIVE
To elucidate disease-specific molecular changes occurring in osteoarthritis (OA) by analysing the differential gene expression profiles of bone marrow mesenchymal stem cells (BM-MSCs) from patients with OA compared with those without OA.


METHODS
Expression profiles of BM-MSCs from eight paired patients with OA and patients with hip fracture without signs of OA were compared by DNA microarray expression analysis and significant differences were evaluated by computational Gene Set Enrichment Analysis. To validate the involvement of COL10A1 as part of the most downregulated gene set in OA, three tagging single nucleotide polymorphisms were genotyped in 191 patients with OA and 283 controls. COL10A1 expression was also assessed by quantitative RT-PCR in additional subjects.


RESULTS
Expression levels in 9% (1967) of the overall transcripts were significantly different (p<0.05) between MSCs from patients with OA and controls (532 genes reached twofold differences: 240 were upregulated and 292 were downregulated). Cell development and differentiation were the functional categories accounting for most genes with altered expression. Interestingly, several genes related to the Wnt/-catenin pathway and collagen genes were downregulated in MSCs from patients with OA. The collagen gene set was clearly downregulated in OA. Furthermore, the expression of COL10A1 was significantly reduced in patients with OA. A genetic association between the COL10A1 rs11965969 polymorphism and OA was also found.


CONCLUSIONS
COL10A1 downregulation seems to have a role in the establishment of a defective and/or unstable subchondral cartilage matrix in OA disease. It is proposed that OA may be linked to the intrinsic defective regenerative potential of BM-MSCs resulting from its reduced expression of fate commitment-related genes.
Lamas
José Ramón
JR
Rheumatology Service, Hospital Clínico San Carlos, C/ Profesor Martín Lagos s/n, Madrid 28040, Spain. jrlamas@gmail.com
Rodríguez-Rodríguez
Luis
L
Vigo
Ana G
AG
Alvarez-Lafuente
Roberto
R
López-Romero
Pedro
P
Marco
Fernando
F
Camafeita
Emilio
E
Dopazo
Ana
A
Callejas
Sergio
S
Villafuertes
Esther
E
Hoyas
José Antonio
JA
Tornero-Esteban
María Pilar
MP
Urcelay
Elena
E
Fernández-Gutiérrez
Benjamín
B
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001854:Bone Marrow Cells / Q000378:metabolism*; D002478:Cells, Cultured; D016000:Cluster Analysis; D024121:Collagen Type X / Q000096:biosynthesis / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D024121:Collagen Type X