The ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) are a group of proteases that are found both in mammals and invertebrates. Since the prototype ADAMTS-1 was first described in 1997, there has been a rapidly expanding body of literature describing this gene family and the proteins they encode. The complete human family has 19 ADAMTS genes, together with three members of a newly identified subgroup, the ADAMTSL (ADAMTS-like) proteins, which have several domains in common with the ADAMTSs. The ADAMTSs are extracellular, multidomain enzymes whose known functions include: (i) collagen processing as procollagen N-proteinase; (ii) cleavage of the matrix proteoglycans aggrecan, versican and brevican; (iii) inhibition of angiogenesis; and (iv) blood coagulation homoeostasis as the von Willebrand factor cleaving protease. Roles in organogenesis, inflammation and fertility are also apparent. Recently, some ADAMTS genes have been found to show altered expression in arthritis and various cancers. This review highlights progress in understanding the structural organization and functional roles of the ADAMTSs in normal and pathological conditions.

Objective. To profile the expression of all known members of the matrix metalloproteinase (MMP), ADAMTS, and tissue inhibitor of metalloproteinases (TIMP) gene families in normal cartilage and cartilage from patients with osteoarthritis (OA).Methods. Human cartilage was obtained from femoral heads at joint replacement for OA or following fracture to the femoral neck. Total RNA was purified, and gene expression was assayed using quantitative real-time polymerase chain reaction.Results. Several members of the above gene families were regulated in OA. Genes that showed increased expression in OA were MMP13, MMP28, and ADAMTS16 (all at P < 0.001), MMP9, MMP16, ADAMTS2, and ADAMTS14 (all at P < 0.01), and MMP2, TIMP3, and ADAMTS12 (all at P < 0.05). Genes with decreased expression in OA were MMP1, MMP3, and ADAMTS1 (all at P < 0.001), MMP10, TIMP1, and ADAMTS9 (all at P < 0.01), and TIMP4, ADAMTS5, and ADAMTS15 (all at P < 0.05). Correlation analysis revealed that groups of genes across the gene families were coexpressed in cartilage.Conclusion. This is the first comprehensive expression profile of all known MMP, ADAMTS, and TIMP genes in cartilage. Elucidation of patterns of expression provides a foundation with which to understand mechanisms of gene regulation in OA and potentially to refine the specificity of antiproteolytic therapies.Osteoarthritis (OA) is a debilitating disease that affects ϳ80% of people over the age of 65 (1). Given the current demographic trend toward an older population, OA, for which age is an important risk factor (2), will be an increasing health and economic burden on society.Degradation of articular cartilage is a major feature of OA. Cartilage is made up of 2 main extracellular matrix (ECM) macromolecules, type II collagen and aggrecan, a large aggregating proteoglycan (3,4). The type II collagen scaffold endows the cartilage with its tensile strength, while the aggrecan, by virtue of its high negative charge, swells against the collagen network as it draws water into the tissue, enabling it to resist compression. Quantitatively more minor components (e.g., types IX, XI, and VI collagen, biglycan, decorin, cartilage oligomeric matrix protein, etc.) also have important roles in controlling matrix structure and organization (5).Normal cartilage ECM is in a state of dynamic equilibrium, with a balance between synthesis and degradation. For the degradative process there is a balance between proteinases that degrade the ECM and their inhibitors. It is generally believed that in OA, a disruption of this balance, in favor of proteolysis, leads to pathologic cartilage destruction.The matrix metalloproteinases (MMPs) are a family of 23 enzymes in humans which facilitate ECM turnover and breakdown under normal and disease conditions (6). The MMP family contains the only mammalian proteinases that can specifically degrade triple-helical collagens at neutral pH. These so-called collagenases specifically cleave a single locus in all 3 collagen chains at a point three-quarters from the N-terminus of...

The adamalysin-thrombospondin (ADAMTS) proteinases are a relatively newly described branch of the metzincin family that contain metalloproteinase, disintegrin, and thrombospondin motifs. They have been implicated in various cellular events, including cleavage of proteoglycans, extracellular matrix degradation, inhibition of angiogenesis, gonadal development, and organogenesis. However, in many cases, their normal physiological roles and their potential for dysregulation in malignancy remain to be established. The expression profile of ADAMTS1-20 in human breast carcinoma was undertaken by real-time PCR using RNA isolated from malignant tumors, nonneoplastic mammary tissue, and breast cancer cell lines to identify altered regulation that may have potential pathogenetic and prognostic significance. Our studies show that seven of the ADAMTS genes (ADAMTS1, 3, 5, 8, 9, 10, and 18) are consistently downregulated in breast carcinomas with respect to nonneoplastic mammary tissue, irrespective of the heterogeneity of the samples and the tumor type or grade (Mann-Whitney U test, P < 0.0001 for each gene). Conversely, ADAMTS4, 6, 14, and 20 are consistently up-regulated in breast carcinomas (P ‫؍‬ 0.005, P < 0.0001, P ‫؍‬ 0.003, and P ‫؍‬ 0.001, respectively). ADAMTS2, 7, 12, 13, 15, 16, 17, and 19 show no significant difference between the sample types. ADAMTS1, 2, 7, 8, 10, and 12 are expressed predominantly in stromal fibroblasts. ADAMTS3, 4, 5, 6, 9, and 13-20 inclusive are expressed predominantly in myoepithelial cells; all appear to be relatively poorly expressed in luminal epithelial cells. ADAMTS15 has emerged as being an independent predictor of survival, with RNA expression levels significantly lower (P ‫؍‬ 0.007) in grade 3 breast carcinoma compared with grade 1 and 2 breast carcinoma.

Articular cartilage is a highly specialized tissue that covers the surface of synovial joints, allowing its smooth articulation. Cartilage is synthesized and maintained by chondrocytes, and is composed primarily of water, proteoglycan (principally aggrecan), and collagen (1). Type II collagen fibrils are arranged to form a fibrillar network within which are trapped aggrecan molecules that pull water into the tissue. These two components provide cartilage with its tensile strength and the ability to resist compression. The degradation of cartilage is one of the key features of the arthritides and results in disability.The degradation of cartilage in vitro and in vivo is believed to be mediated by neutral endopeptidases of the metalloproteinase class of enzymes (2). Two families in this class that have been implicated are the matrix metalloproteinase (MMP) and ADAM families (2,3).

We recently undertook expression profiling of all 19 human ADAMTS metalloproteinases (a disintegrin and metalloproteinase with thrombospondin motifs) in malignant and non-neoplastic breast tissue and showed that 11 of the ADAMTS genes are dysregulated in breast carcinoma. We identified a subgroup of ADAMTSs, based on functional and amino acid sequence similarity (ADAMTS1, 4, 5, 8 and 15), to be the focus of further study in breast carcinoma. Further RNA expression analysis by realtime PCR on a different cohort of 229 patients with breast cancer has identified ADAMTS8 as a predictor of poor overall survival (OS) (hazard ratio (HR) 5 2.20, 95% C.I. 5 1.29-3.74, p 5 0.004) and confirmed ADAMTS15 as a predictor of prolonged relapse-free survival (RFS) (HR 5 0.54, 95% C.I. 5 0.32-0.89, p 5 0.016). We explored the differences in survival of the 4 groups that could be categorized based on the expression levels of ADAMTS8 and ADAMTS15. For both RFS and OS, the group with high ADAMTS8 and low ADAMTS15 expression had a particularly poor prognosis. This group had a 3-fold higher chance of recurrence (HR 5 3.03, 95% C.I. 5 1.49-6.15, p 5 0.001) and a greater than 5-fold higher chance of death (HR 5 5.40, 95% C.I. 5 2.16-13.5, p < 0.001) than the most favorable prognostic group. This prediction of poor prognosis by ADAMTS8 and ADAMTS15 expression was found to be independent of other classical clinicopathological factors. Results observed in FVBPyMT mice, a robust transgenic model of highly metastatic breast carcinoma, fitted the expectation that relatively high expression levels of ADAMTS8 together with low expression levels of ADAMTS15 seen in human breast carcinoma are associated with a poor clinical outcome. In summary, ADAMTS8 and ADAMTS15 have emerged as novel predictors of survival in patients with breast carcinoma. ' 2005 Wiley-Liss, Inc.