The role of ADAMTSs in arthritis

Abstract

The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family consists of 19 proteases. These enzymes are known to play important roles in development, angiogenesis and coagulation; dysregulation and mutation of these enzymes have been implicated in many disease processes, such as inflammation, cancer, arthritis and atherosclerosis. This review briefly summarizes the structural organization and functional roles of ADAMTSs in normal and pathological conditions, focusing on members that are known to be involved in the degradation of extracellular matrix and loss of cartilage in arthritis, including the aggrecanases (ADAMTS-4 and ADAMTS-5), ADAMTS-7 and ADAMTS-12, the latter two are associated with cartilage oligomeric matrix protein (COMP), a component of the cartilage extracellular matrix (ECM). We will discuss the expression pattern and the regulation of these metalloproteinases at multiple levels, including their interaction with substrates, induction by pro-inflammatory cytokines, protein processing, inhibition (e.g., TIMP-3, alpha-2-macroglobulin, GEP), and activation (e.g., syndecan-4, PACE-4).

ADAMTS-12 Metalloprotease Is Necessary for Normal Inflammatory Response

“…Diluted blood was then added to 4 ml of Lymphoprep TM and centrifuged for 20 min at 800 relative centrifugal force. After separation, supernatant was removed, and the pellet containing granulocytes and erythrocytes was suspended in 12 ml of erythrocyte lysis buffer (150 mM NH 4 Cl, 10 mM KHCO 3 , 0.1 mM EDTA). After 10 min, this suspension was centrifuged for 5 min at 400 relative centrifugal force; supernatant was removed, and the remaining pellet was washed with 800 l of erythrocyte lysis buffer.…”

“…These thrombospondin domains, together with other ancillary motifs, constitute a region that likely acts by modulating substrate binding, determining cell location or sequestering factors in the extracellular matrix. Some ADAMTSs, such as ADAMTS-4 and ADAMTS-5, have been related to inflammatory-related processes including arthritic diseases (4). Therefore, it is tempting to speculate that the altered function of any of these ADAMTSs putatively involved in inflammation could contribute to the development of a variety of human diseases.…”

Insights into Ectodomain Shedding and Processing of Protein-tyrosine Pseudokinase 7 (PTK7)

“…TIMP-1 is an inefficient inhibitor of MT1-MMP and many ADAMs excluding ADAM10 (k i ϭ 0.1 nM) (40,60). TIMP-2 and, especially TIMP-3 are highly potent inhibitors of MT1-MMP and ADAM17 (40,42,(61)(62)(63)(64)(65). Certain ADAM family members, including ADAM8 and ADAM9, are not inhibited by the TIMPs, including TIMP-4 (66).…”

Role of Metalloproteinases in Tendon Pathophysiology

“…Their structural arrangement is drastically different from that of MMPs (Fig. 4) and these enzymes play an important role in the turnover of extracellular matrix proteins in various tissues, their altered regulation being implicated in diseases such as cancer, arthritis and atherosclerosis [52][53][54]. In particular, ADAMTS5 is expressed by specific cell lineages during embryonic development, such as arterial smooth muscle cells, concomitantly with the appearance in the neuromuscular system of some of its substrates, namely versican and aggrecan [55].…”