Integrated Analysis of MicroRNA and mRNA Expression Profiles in Rheumatoid Arthritis Synovial Monocytes

Jong Dae Ji; Tae-Hwan Kim; Bitnara Lee; Kyung-Sun Na; Sung Jae Choi; Young Ho Lee; Gwan Gyu Song

doi:10.4078/jrd.2011.18.4.253

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Ji, Kim, Lee, Na, Choi, Lee, and Song: Integrated Analysis of MicroRNA and mRNA Expression Profiles in Rheumatoid Arthritis Synovial Monocytes

Original Article

J Rheum Dis 2011;18(4):253-263.

Published online: 31 December 2011

DOI: https://doi.org/10.4078/jrd.2011.18.4.253

Integrated Analysis of MicroRNA and mRNA Expression Profiles in Rheumatoid Arthritis Synovial Monocytes

Jong Dae Ji¹, Tae-Hwan Kim², Bitnara Lee², Kyung-Sun Na³, Sung Jae Choi¹, Young Ho Lee¹, Gwan Gyu Song¹

¹Division of Rheumatology, College of Medicine, Korea University, Seoul, Korea

²The Hospital for Rheumatic Diseases, College of Medicine, Hanyang University, Seoul, Korea

³Kim's Clinic, Seoul, Korea

Correspondence : Jong Dae Ji Division of Rheumatology, Department Internal Medicine, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul 136-705, Korea E-mail : jjdjmesy@korea.ac.kr

Received 2 May 201122 June 2011 Accepted 22 June 2011

Abstract

Objective

MicroRNAs (miRNAs) play important roles in many biological processes and recent studies have provided growing evidences that miRNA dysregulation might play important roles in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to investigate the contribution of miRNAs to altered gene expressions in RA.

Methods

To investigate whether the differential expression of miRNA in RA could account for the altered expression of certain genes, we compared the different expressions of miRNAs and mRNAs in rheumatoid synovial fluid monocytes with that of normal peripheral blood (PB) monocytes by using a gene expression oligonucleotide microarray and a microRNA microarray.

Results

Comparative analysis of the mRNA profiles showed significant different expressions of 430 genes in RA synovial monocytes, of which 303 (70%) were upregulated and 127 (30%) were downregulated, as compared with that of normal PB monocytes. Out of differentially expressed 13 miRNAs, 9 miRNAs were upregulated and 4 miRNAs were downregulated in the RA synovial monocytes. A total of 62 genes were predicted as target genes of the 13 differentially expressed miRNAs in the RA synovial monocytes. Among the 62 miRNA-targeted genes, a few genes such as GSTM1, VIPR1, PADI4, CDA, IL21R, CCL5, IL7R, STAT4, HTRA1 and IL18BP have been reported to be associated with RA.

Conclusion

In the present study, we observed that several miRNAs are differentially expressed in RA synovial monocytes, and we suggest that these different expressions of miRNAs may regulate the expression of several genes associated with the pathogenesis of RA.

Keywords: MicroRNA, Rheumatoid arthritis, Microarray

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Figure 1.

Hierarchical clustering of microRNA expression profile between RA synovial monocytes (RA1-RA6) and normal PB monocytes.

Figure 2.

Validation of the differentially expressed genes and miRNAs in the RA synovial monocytes. The array data for mRNAs (A) and miRNAs (B) was validated by performing quantitative real-time PCR on the normal peripheral blood monocytes from four healthy donors and the rheumatoid arthritis synovial fluid monocytes from twelve patients (RA1-RA12). The data is shown as means± SD. ∗p<0.05.

Table 1.

Clinical and demographic features of the study patients with rheumatoid arthritis

Patients	Sex	Age (years)	Disease duration (years)	ESR (mm/hr)	CRP (mg/l)	Medications
RA1	F	57	1	97	3.72	MTX, PD
RA2	F	53	14	77	5.5	MTX, TAC
RA3	F	33	1	47	2.2	MTX
RA4	F	31	7	No data	No data	PD
RA5	F	67	9	72	1.47	MTX, CYC
RA6	F	31	7	39	0.43	MTX, LEF
RA7	F	69	1	68	1.2	MTX, LEF
RA8	F	65	20	81	1.7	REM
RA9	F	64	2	117	4.6	MTX, SSZ
RA10	M	64	2	69	5.4	MTX, LEF
RA11	F	32	9	52	3.77	SSZ, PD
RA12	F	34	2	87	4.1	MTX, HCQ, SSZ

MTX: methotrexate, PD: prednisolone, TAC: tacrolimus, CYC: cyclosporin, LEF: leflunomide, REM: remicade, SSZ: sulfasalazine, HCQ: hydroxychloroquine

Table 2.

Inverse relationship between microRNA and the target mRNA expression identified in the RA synovial monocytes (upregulated microRNAs)

MicroRNA	Gene symbol	Gene name	MicroRNA fold change	mRNA fold change
hsa-let-7e	CD33	CD33 molecule (CD33), transcript variant 1, mRNA.	2.68	-2.37
	TRAF3IP3	TRAF3 interacting protein 3 (TRAF3IP3), mRNA.		-2.93
	PISD	Phosphatidylserine decarboxylase (PISD), mRNA.		-2.06
	CD300LF	CD300 molecule-like family member f (CD300LF), mRNA.		-2.08
hsa-miR-125a-3p	NME3	Non-metastatic cells 3, protein expressed in (NME3), mRNA.	3.81	-2.04
	TRAF3IP3	TRAF3 interacting protein 3 (TRAF3IP3), mRNA.		-2.93
	VIPR1	Vasoactive intestinal peptide receptor 1 (VIPR1), mRNA.		-3.52
	GSTM2	Glutathione S-transferase M2 (muscle) (GSTM2), mRNA.		-6.95
	GSTM1	Glutathione S-transferase M1 (GSTM1), transcript variant 1, mRNA.		-5.13
hsa-miR-155^∗	IL11RA	Interleukin 11 receptor, alpha (IL11RA), transcript variant 1, mRNA.	8.90	-2.21
	TESC	Tescalcin (TESC), mRNA.		-3.64
	SCPEP1	Serine carboxypeptidase 1 (SCPEP1), mRNA.		-2.13
	TRAF3IP3	TRAF3 interacting protein 3 (TRAF3IP3), mRNA.		-2.93
	CD52	CD52 molecule (CD52), mRNA.		-3.03
hsa-miR-34a	IL11RA	Interleukin 11 receptor, alpha (IL11RA), transcript variant 1, mRNA.	4.11	-2.21
	NME3	Non-metastatic cells 3, protein expressed in (NME3), mRNA.		-2.04
	CDA	Cytidine deaminase (CDA), mRNA.		-2.89
	ZNF467	Zinc finger protein 467 (ZNF467), mRNA.		-2.28
	TRAF3IP3	TRAF3 interacting protein 3 (TRAF3IP3), mRNA.		-2.93
	PADI4	Peptidyl arginine deiminase, type IV (PADI4), mRNA.		-20.95
hsa-miR-34a^∗	CSTA	Cystatin A (stefin A) (CSTA), mRNA.	7.48	-3.24
	NFE2	Nuclear factor (erythroid-derived 2), 45kDa (NFE2), mRNA.		-3.74
	CD33	CD33 molecule (CD33), transcript variant 1, mRNA.		-2.37
	SCPEP1	Serine carboxypeptidase 1 (SCPEP1), mRNA.		-2.13
	CD300LF	CD300 molecule-like family member f (CD300LF), mRNA.		-2.08
	GSTM2	Glutathione S-transferase M2 (muscle) (GSTM2), mRNA.		-6.95
hsa-miR-511	C14orf159	Chromosome 14 open reading frame 159 (C14orf159), mRNA.	17.72	-2.11
	ALDH1A1	Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), mRNA.		-2.80
	GSTM2	Glutathione S-transferase M2 (muscle) (GSTM2), mRNA.		-6.95
hsa-miR-642	C6orf192	Chromosome 6 open reading frame 192 (C6orf192), mRNA.	3.79	-2.87
	SLC44A2	Solute carrier family 44, member 2 (SLC44A2), mRNA.		-2.63
	CDH23	Cadherin-like 23 (CDH23), transcript variant 1, mRNA.		-2.13
	PISD	Phosphatidylserine decarboxylase (PISD), mRNA.		-2.06
hsa-miR-92b^∗	CIDEB	Cell death-inducing DFFA-like effector b (CIDEB), mRNA.	2.03	-3.20
	YPEL3	Yippee-like 3 (Drosophila) (YPEL3), mRNA.		-2.52
	PISD	Phosphatidylserine decarboxylase (PISD), mRNA.		-2.06
	GSTM2	Glutathione S-transferase M2 (muscle) (GSTM2), mRNA.		-6.95
	CD79B	CD79b molecule, immunoglobulin-associated beta (CD79B), transcript variant 3, mRNA.		-2.21
	GSTM1	Glutathione S-transferase M1 (GSTM1), transcript variant 1, mRNA.		-5.13
hsa-miR-99b	CFP	Complement factor properdin (CFP), mRNA.	6.53	-3.59
	ATG16L2	ATG16 autophagy related 16-like 2 (S. cerevisiae) (ATG16L2), mRNA.		-3.33
	IL11RA	Interleukin 11 receptor, alpha (IL11RA), transcript variant 1, mRNA.		-2.21
	MLKL	Mixed lineage kinase domain-like (MLKL), mRNA.		-2.10

Table 3.

Inverse relationship between microRNA and the target mRNA expression identified in RA synovial monocytes (downregulated microRNAs)

MicroRNA	Gene symbol	Gene name	MicroRNA fold change	mRNA fold change
hsa-miR-487b	ADFP	Adipose differentiation-related protein (ADFP), mRNA.	-4.71	2.47
	ANKRD9	Ankyrin repeat domain 9 (ANKRD9), mRNA.		3.49
	COLEC12	Collectin sub-family member 12 (COLEC12), mRNA.		7.65
	IDS	Iduronate 2-sulfatase (Hunter syndrome) (IDS), transcript variant 1, mRNA.		2.37
	IL21R	Interleukin 21 receptor (IL21R), transcript variant 2, mRNA.
	MGAT4A	Mannosyl (alpha-1,3-)-glycoprotein beta-1,4-N-acetylglucosaminyltransf-erase, isozyme A (MGAT4A), mRNA.		2.62
				3.68
	NEK6	NIMA (never in mitosis gene a)-related kinase 6 (NEK6), mRNA.
	PRDX1	Peroxiredoxin 1 (PRDX1), transcript variant 2, mRNA.		2.77
	SMAD6	SMAD family member 6 (SMAD6), mRNA.		2.22
hsa-miR-335^∗	ANKRD37	Ankyrin repeat domain 37 (ANKRD37), mRNA.		2.62
	ANTXR1	Anthrax toxin receptor 1 (ANTXR1), transcript variant 3, mRNA.	-3.22	2.39
	BCAR3	Breast cancer anti-estrogen resistance 3 (BCAR3), mRNA.		2.38
	CCL5	Chemokine (C-C motif) ligand 5 (CCL5), mRNA.		2.85
	DHRS3	Dehydrogenase/reductase (SDR family) member 3 (DHRS3), mRNA.		6.95
	GPRIN3	GPRIN family member 3 (GPRIN3), mRNA.		8.43
	IL7R	Interleukin 7 receptor (IL7R), mRNA.		2.51
	OLFML2B	Olfactomedin-like 2B (OLFML2B), mRNA.		6.78
	STAT4	Signal transducer and activator of transcription 4 (STAT4), mRNA.		5.26
	ZMYND15	Zinc finger, MYND-type containing 15 (ZMYND15), mRNA.		2.98
hsa-miR-584	ADAMDEC1	1 ADAM-like, decysin 1 (ADAMDEC1), mRNA.		2.41
	AVPI1	Arginine vasopressin-induced 1 (AVPI1), mRNA.	-3.07	2.85
	BAG3	BCL2-associated athanogene 3 (BAG3), mRNA.		7.52
	MRAS	Muscle RAS oncogene homolog (MRAS), transcript variant 1, mRNA.		2.84
	P4HA2	Procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), alpha polypeptide II (P4HA2), transcript variant 3, mRNA.		2.12
				2.29
	PHACTR1	Phosphatase and actin regulator 1 (PHACTR1), mRNA.
	PRDX1	Peroxiredoxin 1 (PRDX1), transcript variant 2, mRNA.		2.21
	YWHAH	Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta polypeptide (YWHAH), mRNA.		2.22
				3.8
hsa-miR-495	BCAT1	Branched chain aminotransferase 1, cytosolic (BCAT1), mRNA.
	C17orf58	Chromosome 17 open reading frame 58 (C17orf58), transcript variant 2, mRNA.	-2.34	4.21
	FASN	Fatty acid synthase (FASN), mRNA.		2.01
	HTRA1	HtrA serine peptidase 1 (HTRA1), mRNA.		2.06
	IL18BP	Interleukin 18 binding protein (IL18BP), transcript variant A, mRNA.		2.41
	P4HA2	Procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), alpha polypeptide II (P4HA2), transcript variant 3, mRNA.		3.77
				2.29
	PEA15	Phosphoprotein enriched in astrocytes 15 (PEA15), mRNA.		2.6
	TMEM51	Transmembrane protein 51 (TMEM51), mRNA.		11.42
	TUBA1C	Tubulin, alpha 1c (TUBA1C), mRNA.		3.1

Table 4.

Roles of the differentially expressed mRNAs in the RA synovial monocytes

Gene symbol	MicroRNA	Roles in rheumatoid arthritis	Refrences
Decreased
GSTM1	hsa-miR-125a-3p, hsa-miR-92b^∗	The presence of a functional allele for GSTM1 associated with a reduced risk of RA	14,15
VIPR1	hsa-miR-125a-3p	Deficient expression in RA patients associated with the predominant proinflammatory Th1 milieu	16,17
PADI4	hsa-miR-34a	Citrullination of selected substrates may end up in dampening of inflammation at the sites of PAD activity	19
		PAD4 contributes to the generation of ACPA specific substrates and is itself a target of autoantibodies in RA.	18
CDA	hsa-miR-34a	Cytidine deaminase levels are raised in serum and synovial fluid in rheumatoid arthritis (RA)	20
Increased
IL21R	hsa-miR-487b	IL-21R is expressed in RA synovium by RASFs and synovial macrophages	21,22
CCL5	hsa-miR-335^∗	RANTES is overexpressed in RA SF	23
IL7R	hsa-miR-335^∗	Enhanced expression of IL-7Ralpha in RA patients contributes significantly to the joint inflammation	24
STAT4	hsa-miR-335^∗	STAT4, and Jak3 protein expression was generally increased in inflammatory arthritis	25
		A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis	26,29
HTRA1	hsa-miR-495	HtrA1 contributes to the destruction of extracellular matrix through both direct and indirect mechanisms	27
IL18BP	hsa-miR-495	IL18BP levels were raised in RA	28

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