Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of articular cartilage because of extracellular matrix breakdown is the hallmark of arthritis. Degradative fragments of cartilage oligomeric matrix protein (COMP), a prominent noncollagenous matrix component in articular cartilage, have been observed in the cartilage, synovial fluid, and serum of arthritis patients. The molecular mechanism of COMP degradation and the enzyme(s) responsible for it, however, remain largely unknown. ADAMTS-12 (a disintegrin and metalloprotease with thrombospondin motifs) was shown to associate with COMP both in vitro and in vivo. ADAMTS-12 selectively binds to only the epidermal growth factor-like repeat domain of COMP of the four functional domains tested. The four C-terminal TSP-1-like repeats of ADAMTS-12 are shown to be necessary and sufficient for its interaction with COMP. Recombinant ADAMTS-12 is capable of digesting COMP in vitro. The COMP-degrading activity of ADAMTS-12 requires the presence of Zn2+ and appropriate pH (7.5-9.5), and the level of ADAMTS-12 in the cartilage and synovium of patients with both osteoarthritis and rheumatoid arthritis is significantly higher than in normal cartilage and synovium. Together, these findings indicate that ADAMTS-12 is a new COMP-interacting and -degrading enzyme and thus may play an important role in the COMP degradation in the initiation and progression of arthritis.
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PMID:ADAMTS-12 associates with and degrades cartilage oligomeric matrix protein. 1661 30

Loss of articular cartilage caused by extracellular matrix breakdown is the hallmark of arthritis. Degradative fragments of cartilage oligomeric matrix protein (COMP) have been observed in arthritic patients. ADAMTS-7 and ADAMTS-12, two members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, have been associated with COMP degradation in vitro, and are significantly overexpressed in the cartilage and synovium of patients with rheumatoid arthritis. Recent studies have demonstrated the importance of COMP degradation by ADAMTS-7 and ADAMTS-12. Specifically, the size of COMP fragments generated by ADAMTS-7 or ADAMTS-12 is similar to that of COMP-degradative fragments seen in arthritic patients. In addition, antibodies against ADAMTS-7 or ADAMTS-12 dramatically inhibit tumor necrosis factor-induced and interleukin-1beta-induced COMP degradation in cartilage explants. Furthermore, suppression of ADAMTS-7 or ADAMTS-12 expression using the small interfering RNA silencing approach in human chondrocytes markedly prevents COMP degradation. COMP degradation mediated by ADAMTS-7 and ADAMTS-12 is inhibited by alpha(2)-macroglobulin. More significantly, granulin-epithelin precursor, a newly characterized chondrogenic growth factor, disturbs the interaction between COMP and ADAMTS-7 and ADAMTS-12, preventing COMP degradation by these enzymes. This Review summarizes the evidence demonstrating that ADAMTS-7 and ADAMTS-12 are newly identified enzymes responsible for COMP degradation in arthritis, and that alpha(2)-macroglobulin and granulin-epithelin precursor represent their endogenous inhibitors.
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PMID:The role of ADAMTS-7 and ADAMTS-12 in the pathogenesis of arthritis. 1909 27

The mouse strain CBA/CaH-T(14;15)6Ca/J carries a homozygous balanced reciprocal translocation between mouse chromosomes 14 and 15, but the break points of this translocation have not previously been examined in detail. Using fluorescent in situ hybridization, we assigned the break point in 14qE3 to a 200-kb region devoid of any known gene. We similarly defined the break point in 15qA1 to a 27-kb region containing involving ADAMTS12. The chromosomal break likely is between exons 2 and 3 of ADAMTS12. This gene encodes a disintegrin and metalloproteinase with thrombospondin motifs, and this product plays crucial roles in both vascularization and cancer progression and has been implicated in the development of arthritis. The CBA/CaH-T(14;15)6Ca/J mouse strain likely is a suitable model for further examination of the influences of defective ADAMTS12 in various pathologic processes.
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PMID:The t(14,15) in mouse strain CBA/CaH-T(14;15)6Ca/J causes a break in the ADAMTS12 gene. 2041 86

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).
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PMID:The role of ADAMTSs in arthritis. 2120 96

a disintegrin and metalloproteinase (ADAM) with thrombospondin type 1 motif 12 (ADAMTS12) is a degradative enzyme that interacts with the degradable fragments of cartilage oligomeric matrix protein, which is a prominent non-collagenous matrix component in articular cartilage. ADAMTS12 has been observed in the cartilage, synovial fluid and serum of arthritic patients, and may play an important role in the pathogenesis of arthritis. In the present study, we investigated whether genetic polymorphisms of ADAMTS12 are associated with rheumatoid arthritis (RA). To observe the association between ADAMTS12 and RA, we genotyped three single nucleotide polymorphisms (SNPs) (rs1364044, intron C/T; rs10461703, intron C/T; rs25754, missense Thr1495Ile) of ADAMTS12 using a direct sequencing method in 303 RA patients and 495 control subjects. Multiple logistic regression models were performed to analyze the genetic data. SNPStats and SNPAnalyzer Pro programs were used to estimate the odds ratios, 95% confidence intervals and p-values. Bonferroni's correction (pc) was conducted to obtain a defined result. Of the three SNPs, the genotype frequency of rs10461703 was associated with the development of RA (pc=0.0024 in the co-dominant model; pc=0.0009 in the dominant model; pc=0.0006 in the log-additive model). The allele frequency of rs10461703 also showed a significant difference between RA and controls (pc<0.0001). The C allele frequency of rs10461703 was lower in the RA group (36.6%) compared to the control group (45.7%), whereas the T allele frequency of rs10461703 in the RA group (63.4%) was higher compared to that in the control group (54.3%). The other two SNPs (rs1364044 and rs25754) were not associated with the development of RA. However, we did not find any association between the three tested SNPs and RA patients according to clinical features, including erythrocyte sedimentation rate, C-reactive protein level, rheumatoid factor (+ and -) and bone erosion (+ and -). Our results suggest that ADAMTS12 may be a susceptibility gene for RA development.
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PMID:Association of ADAMTS12 polymorphisms with rheumatoid arthritis. 2250 77

ADAMTS-12 is a member of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family of proteases, which were known to play important roles in various biological and pathological processes, such as development, angiogenesis, inflammation, cancer, arthritis, and atherosclerosis. In this review, we briefly summarize the structural organization of ADAMTS-12; concentrate on the emerging role of ADAMTS-12 in several pathophysiological conditions, including intervertebral disc degeneration, tumorigenesis and angioinhibitory effects, pediatric stroke, gonad differentiation, trophoblast invasion, and genetic linkage to schizophrenia and asthma, with special focus on its role in arthritis and inflammation; and end with the perspective research of ADAMTS-12 and its potential as a promising diagnostic and therapeutic target in various kinds of diseases and conditions.
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PMID:ADAMTS-12: a multifaced metalloproteinase in arthritis and inflammation. 2487 75

The a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) comprise a family of secreted zinc metalloproteinases with a precisely ordered modular organization. These enzymes play an important role in the turnover of extracellular matrix proteins in various tissues and their dysregulation has been implicated in disease-related processes such as arthritis, atherosclerosis, cancer, and inflammation. ADAMTS-7 and ADAMTS-12 share a similar domain organization to each other and form a subgroup within the ADAMTS family. Emerging evidence suggests that ADAMTS-7 and ADAMTS-12 may play an important role in the development and pathogenesis of various kinds of diseases. In this review, we summarize what is currently known about the roles of these two metalloproteinases, with a special focus on their involvement in chondrogenesis, endochondral ossification, and the pathogenesis of arthritis, atherosclerosis, and cancer. The future study of ADAMTS-7 and ADAMTS-12, as well as the molecules with which they interact, will help us to better understand a variety of human diseases from both a biological and therapeutic standpoint.
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PMID:The emerging roles of ADAMTS-7 and ADAMTS-12 matrix metalloproteinases. 2778 86