Oncostatin M in combination with tumour necrosis factor   induces a chondrocyte membrane associated aggrecanase that is distinct from ADAMTS aggrecanase-1 or -2

Wang, Hui; Barksby, H. E.; Young, David A.; Cawston, TE; McKie, Norman; Rowan, AD

doi:10.1136/ard.2004.028191

Cited by 35 publications

(36 citation statements)

References 63 publications

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“…The prodomain of human and mouse ADAMTS-5 contains three potential furin recognition sites (Hurskainen et al, 1999) within a multibasic sequence 258 RRRRR 262 ( Fig. 1) and although the predicted activating cleavage at R 262 263 S is detected in an in vitro expression system (Zeng et al, 2006), activation by cleavage at this site has not been confirmed in vivo.…”

Section: Structural Domains Of Adamts-5mentioning

confidence: 99%

“…The disintegrin domain lacks the classical integrin binding sequence (RGD) (Ruoslahti and Pierschbacher, 1986) and does not interact with integrins. The first TS module located C-terminal to the disintegrin domain is highly conserved within the ADAMTS family, including the CSR(T/S)C pentapeptide and conservation of selected glycine, tryptophan and proline residues (Hurskainen et al, 1999). The cysteine rich-region contains ten cysteine residues that are also highly conserved in ADAMTS enzymes.…”

Section: Structural Domains Of Adamts-5mentioning

confidence: 99%

“…It has no cysteine residues, which possibly makes it more flexible than other regions of the molecule. The second TS module located at the C-terminus is less conserved among the ADAMTS enzymes than the first TS module, even though the spacing and number of cysteine residues is strictly conserved (Hurskainen et al, 1999). ADAMTS-5 is predicted to contain four N-glycosylation sites ; one located in the disintegrin domain, one in the cysteinerich region and two in the spacer domain, and they are conserved in mouse and human.…”

Section: Structural Domains Of Adamts-5mentioning

confidence: 99%

“…Human and mouse ADAMTS-5 are 89% identical at the amino acid level. They are located on chromosomes 21 and 16 respectively (Hurskainen et al, 1999). ADAMTS-5: The story so far…”

Section: Structural Domains Of Adamts-5mentioning

confidence: 99%

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ADAMTS-5: The story so far

Fosang

Rogerson²,

East³

et al. 2008

eCM

101

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The recent discovery of ADAMTS-5 as the major aggrecanase in mouse cartilage came as a surprise. A great deal of research had focused on ADAMTS-4 and much less was known about the regulation, expression and activity of ADAMTS-5. Two years on, it is still not clear whether ADAMTS-4 or ADAMTS-5 is the major aggrecanase in human cartilage. On the one hand there are in vitro studies using siRNA, neutralising antibodies and immunoprecipitation with anti-ADAMTS antibodies that suggest a significant role for ADAMTS-4 in aggrecanolysis. On the other hand, ADAMTS-5 (but not ADAMTS-4)-deficient mice are protected from cartilage erosion in models of experimental arthritis, and recombinant human ADAMTS-5 is substantially more active than ADAMTS-4. The activity of both enzymes is modulated by C-terminal processing, which occurs naturally in vivo. The most interesting finding to emerge from our comparison of ADAMTS-5 and ADAMTS-4 is that in terms of gene regulation, these two enzymes are the antitheses of each other. In most cases, ADAMTS-5 is constitutively expressed in human chondrocytes and synovial fibroblasts, whereas ADAMTS-4 expression is induced by proinflammatory cytokines. This paper reviews the data on ADAMTS-5 so far. It represents a snapshot in time of a field that is fast-moving and very exciting.

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Section: Structural Domains Of Adamts-5mentioning

confidence: 99%

Section: Structural Domains Of Adamts-5mentioning

confidence: 99%

Section: Structural Domains Of Adamts-5mentioning

confidence: 99%

“…Human and mouse ADAMTS-5 are 89% identical at the amino acid level. They are located on chromosomes 21 and 16 respectively (Hurskainen et al, 1999). ADAMTS-5: The story so far…”

Section: Structural Domains Of Adamts-5mentioning

confidence: 99%

See 2 more Smart Citations

ADAMTS-5: The story so far

Fosang

Rogerson²,

East³

et al. 2008

eCM

101

View full text Add to dashboard Cite

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“…Previous studies investigating arthritis and OA with ADAMTS4/5 knockout mice have revealed that inhibition of ADAMTS5, but not ADAMTS4, mitigates aggrecan degradation and cartilage destruction, suggesting that ADAMTS5 has an important function in aggrecan degradation in mice (20)(21)(22). However, in human chondrocytes, ADAMTS4 is upregulated by interleukin (IL)-1, tumor necrosis factor α, oncostatin M and transforming growth factor β, indicating that ADAMTS4 functions as the primary aggrecanase in human OA cartilage (4,8,9,(23)(24)(25). The results of the present study, with regard to the mRNA expression of ADAMTS4 in human OA chondrocytes under monolayer culture, provide the first indications that OPN selectively inhibits ADAMTS4 expression, while the expression of ADAMTS5 is not affected by OPN.…”

Section: Discussionmentioning

confidence: 81%

Effect of osteopontin on the mRNA expression of ADAMTS4 and ADAMTS5 in chondrocytes from patients with knee osteoarthritis

Gao

Zeng

Song

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Previous studies have demonstrated that osteopontin (OPN) levels are elevated in the synovial fluid and articular cartilage, and are associated with the severity of knee osteoarthritis (OA). However, the role of OPN in the pathogenesis of OA has yet to be elucidated. The present study aimed to investigate the effects of OPN on the expression of the aggrecanases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)4 and ADAMTS5, in human OA chondrocytes, as they serve a key function in aggrecan degradation. Human OA chondrocytes were obtained from the knees of 16 patients with OA, and subsequently cultured in a monolayer. The chondrocytes were divided into three groups, which included the control (no treatment), N-OPN (treated with 100 ng/ml OPN, the normal circulating OPN concentration) and the H-OPN groups (treated with 1 µg/ml OPN, a high OPN concentration). Reverse transcription-quantitative polymerase chain reaction was performed to quantify the relative mRNA expression levels of ADAMTS4, ADAMTS5 and aggrecan in the chondrocytes. The mRNA expression levels of ADAMTS4 were significantly reduced in the N-OPN and H-OPN groups when compared with the control group (P<0.0001). In addition, the mRNA expression levels of ADAMTS4 were lower in the H-OPN group when compared with the N-OPN group (P<0.001). However, no statistically significant difference was observed in the relative mRNA expression levels of ADAMTS5 among the three groups (P>0.05). Furthermore, the mRNA expression levels of aggrecan were higher in the N-OPN and H-OPN groups when compared with the control group (P<0.0001), and a statistically significant difference was observed between the N-OPN and H-OPN groups with regard to the mRNA expression of aggrecan (P<0.0001). These results demonstrated that OPN may exert a protective effect in human OA chondrocytes against aggrecan degradation by suppressing the expression of ADAMTS4. IntroductionOsteoarthritis (OA) is the most common degenerative disorder of the joint, which is characterized by the progressive loss of articular cartilage. This loss is attributed primarily to the proteolysis of certain structural components within the extracellular matrix (ECM), including proteoglycans and collagens (1-3). Aggrecan is a major component of the cartilage-specific proteoglycans. A number of studies have indicated that the aggrecanase-mediated degradation of aggrecan is a crucial factor in the development of OA (4-7). Aggrecanases are members of the A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, which includes ADAMTS1, 4, 5, 8, 9 and 15, that are expressed in the articular cartilage tissues and chondrocytes of numerous animal species, in addition to humans (8). A previous study indicated that ADAMTS4 and ADAMTS5 were responsible for aggrecan degradation in a human model of OA (9).Osteopontin (OPN) is an ECM glycoprotein that is hypothesized to be a potential inflammatory cytokine. OPN, as a biomarker, has been studied in vivo in rats (10), in healthy h...

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