Abstract
BackgroundThe etiology of Kashin-Beck disease (KBD), an endemic osteochondropathy, is largely unknown. Matrix metalloproteinase-3 (MMP-3) plays a central role in the initiation and progression of cartilage destruction, however, no study has reported on the relationship between KBD and MMP-3. The objective of this study was to explore the polymorphism of MMP-3 gene and expression of MMP-3 / TIMP-1(Tissue inhibitors of matrixmetalloproteinases-1) in the pathogenesis of KBD.MethodsSingle nucleotide polymorphism (SNP) genotyping was conducted in 274 KBD cases and 248 healthy controls for eight SNPs in MMP-3 using the Sequenom MassARRAY system. Additionally, the expression of MMP-3、TIMP-1 in different layers of the articular cartilage was analyzed by immunohistochemistry for 22 KBD patients, 15 osteoarthritis (OA) patients and 21 controls.ResultsThe results showed that six SNPs (rs520540、rs591058、rs679620、rs602128、rs639752 and rs678815) in MMP-3 were associated with the increased risk of KBD, however, after Bonferroni correction, only the SNP rs679620 in the recessive model remained significant difference (OR = 2.31, 95%CI = 1.29–4.14, P = 0.0039), homozygous for “T” allele have a risk for KBD than “C” allele carriers. Moreover, the percentages of cells expressing MMP-3 in articular cartilage were significantly higher in the KBD and OA groups than in the controls (t = 5.37 and 4.19, P<0.01). While the KBD and OA groups had lower levels of TIMP-1 positive staining compared with the controls (t = 5.23and 5.06, P<0.01). And there was no significant different between KBD and OA for the levels of MMP-3 and TIMP-1 positive staining (t = 0.05and 0.28, P>0.05).ConclusionsMMP-3 is associated with the susceptibility of KBD, and the imbalance expression of MMPs / TIMPs leading to cartilage degradation may play an important role in cartilage degradation and osteoarthritis formation in OA and KBD.
Highlights
Kashin-Beck disease (KBD) is a chronic osteochondropathy affecting the bones and joints that is endemic to certain geographical areas of Russia, North Korea and China [1]
Association of polymorphisms of Matrix metalloproteases (MMPs)‐3 with KBD susceptibility Table 1 showed the information of the eight Single nucleotide polymorphism (SNP), all tested SNPs were in Hardy-Weinberg equilibrium (HWE) in control group (x2 = 0.02– 2.41, df = 2, P = 0.29–1.00)
When the allele frequencies were compared between the KBD cases and the controls, no significant association was detected in the eight SNPs (Table 1)
Summary
Kashin-Beck disease (KBD) is a chronic osteochondropathy affecting the bones and joints that is endemic to certain geographical areas of Russia, North Korea and China [1]. The balance between the activity of MMPs and that of TIMPs has been considered to affect the integrity of connective tissue, including cartilage [9]. Studies on the genetic polymorphisms of OA have found that the polymorphisms of MMP-3 promoter 5A / 6A are associated with this disease and MMP-3 is thought to be important in destructive joint change such as OA and RA [10]. Matrix metalloproteinase-3 (MMP-3) plays a central role in the initiation and progression of cartilage destruction, no study has reported on the relationship between KBD and MMP-3. The objective of this study was to explore the polymorphism of MMP-3 gene and expression of MMP-3 / TIMP-1(Tissue inhibitors of matrixmetalloproteinases-1) in the pathogenesis of KBD
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