Association of TIMP-4 gene polymorphism with the risk of osteoarthritis in the Korean population

Abstract

Due to an imbalance in the MMP:TIMP ratio determined a tissue damage in arthritis, it is hypothesized that polymorphic variations of the TIMP genes are associated with regulation of the MMP:TIMP balance. To test this hypothesis, the presence of single nucleotide polymorphisms (SNPs) located in the human TIMP-2 and TIMP-4 genes was confirmed in the Korean RA and OA patients. We performed a case-control study comprising 109 unrelated Korean OA patients, 177 unrelated Korean RA patients and 175 healthy subjects. There were statistically significant differences in the genotype distribution and allele frequencies of the C/T polymorphism of TIMP-4 gene between OA and control groups (P = 0.0002 and P = 0.001, respectively). However, no significant association between TIMP-2 polymorphisms and OA was observed. Also, no difference was observed when allele or genotype frequencies of both TIMP-2 and TIMP-4 gene polymorphisms were compared between RA and controls. We demonstrated that the C/T polymorphism which is located on the 3'-untranslational regions of the TIMP-4 gene might be associated with susceptibility to OA patients.

Enhanced Expression of Tissue Inhibitor of Metalloproteinases-4 Gene in Human Osteoarthritic Synovial Membranes and Its Differential Regulation by Cytokines in Chondrocytes

“…In contrast with the increased TIMP-1, TIMP-2 and TIMP-3, TIMP-4 RNA levels were decreased during early inflammatory phase of healing rabbit ligaments [24]. Single nucleotide polymorphism at the 3’-untranslanted region of TIMP-4 gene has also been associated with susceptibility of Korean patients to OA [25]. …”

Proteases involved in cartilage matrix degradation in osteoarthritis

“…TIMP-2 has no effect on glycosaminoglycan release from bovine, porcine or human cartilage explants, while TIMP-1 has been shown to partially inhibit glycosaminoglycan release from human but not bovine or porcine cartilage [56, 106, 180]. Expression of TIMP-4 is decreased in OA cartilage [61], and a single nucleotide polymorphism in the 3′ untranslated region of TIMP-4 is reportedly associated with OA in a Korean cohort [187]. …”

Tissue Inhibitor of Metalloproteinases-4. The road less traveled

“…In addition, a polymorphism in the region that transcribes the 3' UTR of the TIMP-4 has been identified. The effect of this polymorphism on TIMP-4 expression and function is unknown, however it is associated with a major risk for osteoarthritis in the Korean population [ 49 ]. TIMP-4 function is also regulated by postranslational modifications.…”