ADAMTS4

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A disintegrin and metalloproteinase with thrombospondin motifs 4 is abbreviated as ADAMTS4. The human ADAMTS4 cDNA is located at lq21-23 and consists of 2 511 bases in length and encodes 837 amino acids. ADAMTS is a new type of Zn2+-dependent secretory metalloproteinase that is widely found in mammals and invertebrates. Since the name of ADAMTS in Kuno in 1997, the ADAMTS family has discovered 19 members with similar domains to a disintegrin and metalloproteinase (ADAM) and matrix metalloproteinase (MMP). The molecular structure of members of the ADAMTS family is also extremely similar. In terms of composition, the end of ADAMTS contains thrombin-sensitive protein (TSP), and its domain from N-terminus to C-terminus are signal peptide region, prodomain, metalloproteinase catalytic domain, and dissocial-like domain, TSP repeats, cysteine-rich regions, spacer regions, and TSP repeats.

Function and Regulation of ADAMTS4

ADAMTS4 have been shown to have multiple functions ranging from ovulation, neuroplasticity, and osteoarthritis. Studies using Adamts4-null mice have shown that these mice are phenotypically normal and do not show protection against aggrecan degradation in mouse inflammation or surgically induced arthritis, suggesting that ADAMTS4 is not the primary aggrecanase in mouse arthritis.

Many other ECM proteins have been shown to be substrates for ADAMTS4, including matrilin, hevin, and reelin, which are enriched in the brain. This may mean that ADAMTS4 may have other features that are not yet discovered during the development process. In fact, a recent report suggests that ADAMTS4 has an extraneous and important role in perinatal kidney development. The ADAMTS4 gene promoter contains at least 1 transcription factor 1 binding site and is regulated by the expression of IL-1. Studies have also shown that parthenolide, a regulator of signal transduction and activator of transcription factor 3, inhibits the activity of IL-6/sIL-6R on ADAMTS4.

ADAMTS4 and Angiogenesis

Studies have shown increased expression of ADAMTS4 mRNA in response to VEGF stimulation and strong mRNA ADAMTS4 expression in the vascular endothelium. ADAMTS4 is expressed in HUVEC and human dermal microvascular endothelial cells (HuDMEC). Using a truncated recombinant ADAMTS4 protein lacking the C-terminal region of the protein, it was demonstrated that ADAMTS4 reduces/inhibits HuDMEC differentiation on Matrigel and migration in the scratch healing assay without affecting cell proliferation and viability. Like ADAMTS1, ADAMTS4 appears to also exhibit its anti-angiogenic function, as observed by binding and isolating VEGF and preventing VEGFR2 signaling, such as loss of VEGFR2 phosphorylation.

Dong et al. showed that ADAMTS4 expression is up-regulated during carotid atherosclerotic plaque development. Serum ADAMTS4 levels are associated with increased plaque vulnerability in symptomatic and asymptomatic patients with carotid stenosis. ADAMTS4 may be a potential biomarker for plaque vulnerability.

ADAMTS4 and Cancer

Many of the substrates of ADAMTS4 are proteoglycans that are abundantly present in ECM. Thus, this multi-domain metalloproteinase may play a role in tumor angiogenesis and tumor progression. Increased expression of ADAMTS4 has been observed in several human cancers, such as breast cancer, head and neck squamous cell carcinoma, and human glioblastoma. In Ewings sarcoma, high expression of ADAMTS4 is a potential tumor marker. Preliminary data from the study also indicate extensive expression of the ADAMTS4 protein in human cancers. Using a homologous mouse tumor implanted melanoma model, we demonstrate that catalytically active full-length ADAMTS4 promotes melanoma tumor growth. In contrast, the C-terminal helper region and the full-length protein lacking catalytic activity inhibit tumor growth. The involvement of ADAMTS4 in tumor angiogenesis is closely related to its catalytic activity. Thus, ADAMTS4 is similar to ADAMTS1 with pro-tumorigenic activity and anti-tumorigenic activity produced by its various isoforms. Further research is needed to elucidate the role of this metalloproteinase in human cancers.

Expression and Role of ADAMTS4 in Osteoarthritis

Dancevic et al. showed that ADAMTS4 and ADAMTS5 cleavage (scissors) in the interglobular domain (IGD) of aggrecan are the most unfavorable for cartilage function in arthritis. Cytokine activity inhibitors or ADAMTS5 directly block cartilage loss. Verma et al. developed a chemical-based ADAMTS4 inhibitor pharmacophore model using the HipHop module in the Catalyst package to elucidate structure-activity relationships and perform computer screening. The in vitro inhibitory activities of the 13 compounds were finally evaluated after various screening and filtration procedures for all hits. The results provide insight into the development of more potent pharmacodynamic requirements for ADAMTS4 inhibitors.

Figure 1. The destruction of aggrecan and therapies that slow radiographic progression of arthritis (Dancevic, et al. 2014)

Expression and role of ADAMTS4 in osteoarthritisDancevic et al. showed that ADAMTS4 and ADAMTS5 cleavage (scissors) in the interglobular domain (IGD) of aggrecan are the most unfavorable for cartilage function in arthritis. Cytokine activity inhibitors or ADAMTS5 directly block cartilage loss. Verma et al. developed a chemical-based ADAMTS4 inhibitor pharmacophore model using the HipHop module in the Catalyst package to elucidate structure-activity relationships and perform computer screening. The in vitro inhibitory activities of the 13 compounds were finally evaluated after various screening and filtration procedures for all hits. The results provide insight into the development of more potent pharmacodynamic requirements for ADAMTS4 inhibitors.

Studies have shown that TNF-α, IL-6, and oncostatin M participate in and up-regulate the expression of ADAMTS4 mRNA. Song et al. found that the ability of ADAMTS4 to degrade aggrecan was significantly inhibited by the application of small interfering RNA under the induction of TNF-α and oncostatin M. More importantly, after the small interfering RNA inhibited the activity of ADAMTS4, the degradation of aggrecan was significantly reduced in unstimulated human osteoarthritic cartilage, indicating that ADAMTS4 plays an important role in the structural destruction of osteoarthritis. The study found that ADAMTS4 is expressed in both osteoarthritis and normal human synoviocytes, but is significantly increased by IL-1, TNF-α, and TGF-β.

By studying human normal cartilage and osteoarthritic cartilage, it was found that ADAMTS4 may play a major role in aggrecan degradation of osteoarthritis. The promoter of ADAMTS4 gene CpG site DNA demethylation regulates the expression of ADAMTS4 in articular cartilage. Studies have shown that ADAMTS5 expression is significantly increased in the serum of advanced osteoarthritis, and ADAMTS4 expression is significantly up-regulated in early osteoarthritis serum, indicating that ADAMTS4 has the more significant in the early diagnosis of osteoarthritis than ADAMTS5.