Overexpression of SPACIA1/SAAL1, a newly identified gene that is involved in synoviocyte proliferation, accelerates the progression of synovitis in mice and humans

Abstract

Objective. To identify novel genes associated with dysregulated proliferation of activated synovial fibroblasts, which are involved in arthritic joint destruction.Methods. We performed transcriptome analysis to identify genes that were up-regulated in the foot joints of mice with collagen-induced arthritis (CIA). The effect of candidate genes on proliferation of synovial fibroblasts was screened using antisense oligodeoxynucleotides and small interfering RNAs (siRNAs). We characterized the expression and function of a novel gene, synoviocyte proliferation-associated in collageninduced arthritis 1 (SPACIA1)/serum amyloid A-like 1 (SAAL1) using antibodies and siRNA and established transgenic mice to examine the effect of SPACIA1/ SAAL1 overexpression in CIA.Results. Human and mouse SPACIA1/SAAL1 encoded 474 amino acid proteins that shared 80% homology. SPACIA1/SAAL1 was primarily expressed in the nucleus of rheumatoid arthritis (RA) synovial fibroblasts and was highly expressed in the hyperplastic lining of inflamed synovium. In addition, its expression level in RA-or osteoarthritis (OA)-affected synovial tissue was positively correlated with the thickness of the synovial lining. Furthermore, SPACIA1/SAAL1 siRNA inhibited the proliferation of synovial fibroblasts, especially tumor necrosis factor ␣-induced synovial fibroblasts, by blocking entry into the S phase without inducing apoptosis. Finally, transgenic mice overexpressing SPACIA1/SAAL1 exhibited early onset and rapid progression of CIA.Conclusion. These results suggest that SPACIA1/ SAAL1 is necessary for abnormal proliferation of synovial fibroblasts and its overexpression is associated with the progression of synovitis in mice and humans. Thus, therapy targeting SPACIA1/SAAL1 might have potential as an inhibitor of synovial proliferation in RA and/or OA.Synovitis is a common characteristic of rheumatoid arthritis (RA) and knee osteoarthritis (OA). The major pathologic features of synovitis are hyperplasia of the synovial lining, inflammatory cell infiltration, and

SPACIA1/SAAL1 Deletion Results in a Moderate Delay in Collagen-Induced Arthritis Activity, along with mRNA Decay of Cyclin-dependent Kinase 6 Gene

“…In the previous study using SPACIA1 overexpressing mice, we reported that SPACIA1 is a synovitis modifying factor [7]. In this study, to confirm whether SPACIA1 is essential in the progression of synovitis, arthritis was induced using collagen in the SPACIA1 -deficient mice (Figure 2).…”

“…In our previous study, we identified synoviocyte proliferation-associated in collagen-induced arthritis (CIA) 1/serum amyloid A-like 1 ( SPACIA1/SAAL1 ) as an overexpressed gene in the joint tissue of mice with CIA and indicated that the gene was associated with abnormal synovial proliferation in human RA [7]. We also showed that SPACIA1/SAAL1 small interfering RNA (siRNA) inhibited the proliferation of RA synovial fibroblasts (RASFs) in vitro and that SPACIA1/SAAL1 transgenic mice exhibited early onset and rapid progression of CIA.…”

Identification of the Novel Oncogenic Role of SAAL1 and Its Therapeutic Potential in Hepatocellular Carcinoma

“…Serum amyloid A-like 1 (SAAL1) is a serum amyloid A (SAA) related gene and located in the same chromosome (11p) with SAA family genes [14]. SAAL1 is a novel acute phase responsive protein associated with the dysregulated proliferation of activated synovial fibroblasts to accelerate the progression of synovitis [15]. Upregulation of SAAL1 has been found in the foot joints of mice with collagen-induced arthritis and knockdown of SAAL1 can inhibit the proliferation of human rheumatoid arthritis synovial fibroblast (RASFs) in vitro [15].…”

“…SAAL1 is a novel acute phase responsive protein associated with the dysregulated proliferation of activated synovial fibroblasts to accelerate the progression of synovitis [15]. Upregulation of SAAL1 has been found in the foot joints of mice with collagen-induced arthritis and knockdown of SAAL1 can inhibit the proliferation of human rheumatoid arthritis synovial fibroblast (RASFs) in vitro [15]. Another study using Oplegnathus fasciatus as a model system revealed that the level of SAAL1 was significantly elevated in the blood and liver upon the challenge of bacterial infection [14].…”

Complement Factor H and Apolipoprotein E Participate in Regulation of Inflammation in THP-1 Macrophages

“…After 24 h incubation the THP-1 cell mRNAs were isolated and subjected to sequencing-based transcriptome analysis covering over 27,000 RNA sequences of different genes. Transcriptome analysis resulted in a selection of transcripts that are associated with inflammation, atherosclerosis and the complement system [Table 2 , ( 18 , 39 – 46 )]. When these transcriptomes were compared between the FH and PBS incubated cells some clear effects/differences could be seen between THP-1 macrophages and cholesterol loaded THP-1 macrophages.…”