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A disintegrin and metalloproteinase with thrombospondin motifs 5 is abbreviated as ADAMTS5. The ADAMTS5 gene is located on the human chromosome 21q21.3 and contains 8 exons and 7 introns encoding a protein consisting of 518 amino acids. Compared to the ADAMTS5, the ADAMTS4 has only a C-tap end and a TSP-1 sequence in its structure. There is a second TSP sequence at the C-terminus of ADAMTS5, which may be related to the binding of proteoglycans.
Compared with the ADAM family and the MMP family, ADAMTS lacks the EGF domain, the transmembrane region, the cytoplasmic region, the carboxy-terminal hinge region, and the heme-binding protein region, but has the TSP-1 sequence. TSP-1 is an endogenous angiogenesis inhibitor that blocks angiogenesis and organizes endothelial cell proliferation and migration.
Regulation of ADAMTS5
ADAMTS5 is a 100 kDa secreted matrix metalloproteinase with two TSRs, the central TSR (first TSR) and the C-terminal TSR (second TSR). Like all other ADAMTS members, ADAMTS5 is secreted by its N-terminal signal peptide. The incubation period of the enzyme is maintained by its pre-domain, which is cleaved outside the cell.
The latest studies show that ADAMTS4 and 5 are potential downstream targets for NFATp and RUNX2 transcription factors in soft bone cells, which can regulate proteoglycan degradation by inhibiting the expression and function of NFATp or RUNX2. Histone deacetylase inhibitors inhibit the expression of RUNX2 and ADAMTS5 via the mitogen-activated protein kinase signaling pathway. The Wnt/β-catenin signaling pathway gene COL10A1 and low-density lipoprotein receptor-related protein 1 mediated endocytosis also regulate the activity of the articular cartilage extracellular matrix ADAMTS5. Studies have also shown that the signal transduction and activator of transcription factor 3, parthenolide, inhibits the activity of IL-6/sIL-6R on ADAMTS4 and down-regulates the expression of ADAMTS5.
ADAMTS5 has been shown to help skin wound healing by degrading aggrecan around cells and activating fibrogenic TGF-β1 signaling in fibroblasts. Studies have demonstrated the role of ADAMTS5 in wound healing, suggesting that ADAMTS5 is important for the renewal of cells around the cell and for the regulation of fibroblasts to myofibroblasts. These studies indicate that ADAMTS5 is a key player in various physiological and pathological processes involved in proteoglycan conversion.
Expression and Role of ADAMTS5 in Osteoarthritis
Studies on human normal cartilage and osteoarthritic cartilage have shown that ADAMTS5 is structurally expressed in osteoarthritis. Additional studies have shown that ADAMTS5 is the major aggrecanase and knockdown of the ADAMTS5 gene is effective in inhibiting the degradation of articular cartilage in rat osteoarthritis. By knocking out the ADAMTS4, 5 genes to establish a mouse osteoarthritis model, it was found that mice knocked out of the ADAMTS4, 5 genes had a lower degree of osteoarthritis than mice that only knocked out the ADAMTS5 gene. It is shown that simultaneous inhibition of ADAMTS4, 5 activity can better reduce the severity of osteoarthritis.
By establishing an in vitro cartilage culture system, it was found that aggrecanase is an enzyme involved in the degradation of aggrecan in the early stage of osteoarthritis, and MMP mainly plays a role in the later stage. By inducing cartilage degradation in the articular cartilage separation block with oncostatin M and TNF, it was found that ADAMTS4,5-mediated aggrecan degradation occurs in the early stages of osteoarthritis, MMP-mediated aggrecan and collagen degradation mainly occurs in the later stages.
Figure 1. The structure of the articular joint and targeted arthritis therapeutics. (Dancevic, et al. 2014)
Dancevi et al. have shown that emerging therapeutic agents such as statins inhibit inflammatory cytokine activity in synovial fluid, potentially inhibiting cartilage degradation mediated by ADAMTS4 and ADAMTS5. Disease-modifying anti-rheumatic drugs (DMARDs), biologics, corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) can also prevent cartilage destruction indirectly by reducing inflammation.
Inhibitors and Drug Treatment of ADAMTS5
Members of the ADAMTS family can be effectively inhibited by MMP tissue inhibitors or TIMP, where TIMP-3 inhibits ADAMTS4, 5 with the highest activity. The N-terminal sequence of TIMP-3 selectively inhibits ADAMTS4,5, indicating that TIMP-3 is an endogenous inhibitor of cartilage.
Studies have found that flavonoid luteolin can inhibit the expression of ADAMTS4,5, suggesting that luteolin can be used as a protein activity regulator for the preparation of new cartilage protective mixtures. Paclitaxel and abietic acid inhibit the expression of ADAMTS4, 5. Studies have shown that the efficient recognition of cleavage sites by new epitope antibodies provides an important approach for the study of aggrecanase and MMP.
When the cartilage matrix degenerates, the expression of ADAMTS5 is increased, and the expression of TIMP-3 is relatively insufficient, which causes the proteoglycan hydrolysis to accelerate, leading to degeneration of articular cartilage. Matrilin-3 is a member of the Matrilins family of oligomeric extracellular proteins, mainly present in cartilage, and up-regulates the expression of type II collagen and aggrecan by mediating IL-1 receptor antagonists and down-regulates ADAMTS5 Gene expression. Removal or genetic coding of the mutant cartilage extracellular matrix protein Matrilin-3 can cause early osteoarthritis, indicating that Matrilin-3 has cartilage protective properties.
As the most molecularly important protein in plasma, α2-macroglobulin is an important endogenous inhibitor of ADAMTS4 and 5, and its active site is Met690-Gly691. α2-macroglobulin is able to scavenge endogenous or exogenous proteases in tissues and coordinate proteolytic activity with some protease inhibitors. As an intrinsic cartilage protective substance, FGF-2 can inhibit the expression of ADAMTS5 and delay cartilage degradation. While the cis-1(S),2(R)-amino-2-nonanol compound is a broad-spectrum selective inhibitor of aggrecanase, it plays a significant role in inhibiting proteoglycans. In addition, the protein papilin extracted from Drosophila and the ADAMTS family have a set of homologous structural regions that inhibit protease activity.