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A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12) are members of the disintegrin and metalloproteinases of the thrombospondin motif (ADAMTS) protease family, which are known to play important roles in various biological and pathological processes, such as Development, angiogenesis, inflammation, cancer, arthritis, and atherosclerosis.
ADAMTS12 was first isolated from a cDNA library of human fetal lung tissue. Chromosomal localization of this multidomain metalloproteinase revealed its localization at 5q35. The predicted molecular weight of full-length ADAMTS12 is 177.5 kDa. The mature ADAMTS12 is 175 kDa, probably due to post-translational modifications.
As a member of the ADAMTS family, ADAMTS-12 is capable of degrading extracellular matrix (ECM) and specifically degrading Cartilage oligomeric matrix protein (COMP), releasing COMP for vascular smooth muscle Cell (VSMC) migration and inhibition of adhesion. This leads to thickening of the intima, accelerated plaque formation and increased vulnerability, and promotes the development of acute cerebral infarction. The study found that the ADAMTS-12 gene polymorphism is associated with pediatric stroke and schizophrenia. A study by Darbouret et al. found that a decrease in the level of placental ADAMTS-12 was associated with intrahepatic cholestasis of pregnancy (ICP), suggesting that inflammation may play a role in the pathogenesis.
ADAMTS-12 and Osteoarthritis
Osteoarthritis is characterized by articular cartilage, chondrocyte proliferation and hypertrophy, subchondral bone remodeling, and inflammatory response. It has been reported that ADAMTS-12 acts as a downstream molecule of parathyroid hormone-related peptide (PTHrP) signaling, negatively regulating cartilage formation. ADAMTS-12 was significantly expressed in proliferation and precursor nutrient chondrocytes in wild-type embryo growth plates, whereas ADAMTS-12 was barely detectable in PTHrP(- / -) embryos. Furthermore, in cells overexpressing ADAMTS-12, expression of chondrogenesis was inhibited in both early (collagen II and Sox9) and late (collagen X) marker genes.
It has been reported that in the external digestion experiment, α-2 macroglobulin (α 2 M) acts as a substrate for two ADAMTS-7 and ADAMTS-12, and is capable of effectively protecting COMP degradation by these enzymes. In addition, granulin-epithelial protein precursor (GEP, a newly discovered cartilage growth factor, also known as epithelial, acrogranin, granule protein precursor protein (PGRN) and GP88 / PC cell-derived growth factor) inhibits ADAMTS The role of -12 prevents COMP from passing through two different mechanisms.
In detail, GEP inhibits the induction of ADAMTS12 by inflammatory cytokines such as TNF-α and GEP and can disrupt the association between ADAMTS12 and COMP by direct protein-protein interaction. Wei et al. describe in detail the interaction and interaction of AADAMTS12, COMP, aggrecan, GEP, α2μM and TNF-α in arthritic cartilage degradation. Upregulation of ADAMTS-12 by TNF-α results in degradation of COMP. Furthermore, TGF-β significantly induced ADAMTS-12 in human fetal fibroblasts.
Figure 1. The interplay network in the degradation of extracellular matrix mediated by ADAMTS-12 in arthritis. (Wei, et al. 2014)
The expression of ADAMTS-12 during cartilage formation is regulated by the c-Maf transcription factor. C-MAF, a c-MAF of cells of avian virus oncogene homologs, is a member of the basic leucine zipper (bZIP structure) superfamily. The c-Maf protein binds to a specific DNA sequence called a "Maf recognition element" (MARE) through a basic DNA recognition domain. Furthermore, C-MAF is overexpressed during embryonic development and postnatal growth of hypertrophic chondrocytes and in osteoarthritic chondrocytes, which is similar to the expression pattern of ADAMTS-12. Hong et al. showed that c-Maf and ADAMTS-12 were co-expressed during in vitro cartilage formation. In addition, the c-Maf transcription factor directly binds to the proximal MARE sequence of ADAMTS-12 at position -61 in vitro.
ADAMTS-12 and Inflammation
ADAMTS-12 has also been reported as a key mediator of inflammation, particularly allergic inflammation. Asthma is characterized by a special pattern of inflammation and air/bronchial hyperresponsiveness (AHR / BHR). The role of ADAMTS-12 in this disease was determined by generating asthma OVA and HDM models in ADAMTS-12 deficient mice. It was found that the lack of ADAMTS-12 exacerbates inflammation by inducing Th2 and exacerbates allergen-induced inflammation and airway responses.
The ADAMTS-12 deficient mouse model showed a more severe allergen-induced AHR phenotype compared to its corresponding WT littermates by histological analysis. Furthermore, in allergen-induced mice, T2-skewed markers of inflammatory responses, such as Ag-specific IgE and Ag-specific IgG1, were significantly increased. When assessing the Th1 related marker IgG2a, there appeared to be no difference between the groups. In ADAMTS-12 deficient mice, cytokine levels of IL-4 and IL-13 (typical Th2 cytokines) are highly increased.
ADAMTS-12 deficient mice were used to establish animal models of colitis, endotoxemia, and pancreatitis. ADAMTS-12 deficient mice show more severe inflammation. ADAMTS-12 deficient tissue showed a significant increase in several inflammatory markers at the RNA and protein levels compared to wild-type littermates. In addition, all ADAMTS-12 deficient mouse models exhibited severe inflammatory symptoms with neutrophils in the affected tissues. ADAMTS-12 shows a protective effect in the pathogenesis of inflammation.
ADAMTS-12 and Tumor
Fontanil et al. reported that ADAMTS-12 plays a role in tumorigenesis and angiogenesis inhibition. ADAMTS-12 was found to play a protective role in angiogenesis and cancer progression by using the ADAMTS-12 deficient mouse model. Transplantation of malignant keratinocytes (PDVA cell line) demonstrated increased tumor vascularization and invasion in ADAMTS-12 deficient mice. In addition, this observation was confirmed by computer image analysis. Aortic explant assay and basic fibroblast growth factor (bFGF) injections indicate that ADAMTS-12 is a negative regulator of angiogenesis. Furthermore, overexpression of ADAMTS-12 in breast cancer (MCF7 cell line) leads to a decrease in neovascularization and also an inhibition of angiogenesis. ADAMTS-12 was also found to abolish vascular endothelial growth factor (VEGF-)-induced tubule formation in bovine aortic endothelial cells (BAE). In addition, ADAMTS-12 also inhibited tumor growth in vivo because A549 cells overexpressing ADAMTS-12 were injected into immunodeficient SCID mice, showing a decrease in tumor growth.