Release of hyaluronan and hyaladherins (aggrecan G1 domain and link proteins) from articular cartilage exposed to ADAMTS‐4 (aggrecanase 1) or ADAMTS‐5 (aggrecanase 2)

Chockalingam, Priya; Zeng, Wanyong; Morris, Elizabeth A.; Flannery, Carl R.

doi:10.1002/art.20496

Cited by 47 publications

(39 citation statements)

References 57 publications

(66 reference statements)

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“…Because the slow migrating bands have intact G1 domains, we postulate that enzymes other than proteinases might be responsible for the release of these fragments (50,51). We (52) and others (53,54) have detected concomitant release of hyaluronan, link protein, and aggrecan G1 fragments into conditioned medium of cytokine-treated cartilage explant cultures, consistent with the hypothesis that hyaluronidases may contribute to depolymerization of the aggrecan aggregate (51). Our present data confirms previous work suggesting that proteolytic and non-proteolytic mechanisms of degradation proceed together (50,51), and also that the non-proteolytic mechanism(s) may be more responsive to treatment with retinoic acid given the pattern and distribution of the SELE 1279 and FREEE 1467 bands seen in Fig.…”

Section: Discussionmentioning

confidence: 82%

ADAMTS-5 Deficiency Does Not Block Aggrecanolysis at Preferred Cleavage Sites in the Chondroitin Sulfate-rich Region of Aggrecan

East

Stanton

Golub

et al. 2007

Journal of Biological Chemistry

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In the mouse, proteolysis in the aggrecan interglobular domain is driven by ADAMTS-5, and mice deficient in ADAMTS-5 catalytic activity are protected against aggrecan loss and cartilage damage in experimental models of arthritis. Here we show that despite ablation of ADAMTS-5 activity, aggrecanolysis can still occur at two preferred sites in the chondroitin sulfate-rich region. Retinoic acid was more effective than interleukin-1␣ (IL) in promoting cleavage at these sites in ADAMTS-5-deficient cartilage. These results suggest that cleavage at preferred sites in the chondroitin sulfate-rich region is mediated by ADAMTS-4 or an aggrecanase other than ADAMTS-5. Following retinoic acid or IL-1␣ stimulation of cartilage explants, aggrecan fragments in medium and extracts contained SELE 1279 or FREEE 1467 C-terminal sequences. Some SELE 1279 and FREEE 1467 fragments were retained in the cartilage, with intact G1 domains. Other SELE 1279 fragments were released into the medium and co-migrated with the 374 ALGS neoepitope, indicating they were aggrecanase-derived fragments. In contrast none of the FREEE 1467 fragments released into the medium co-migrated with the 374 ALGS neoepitope, suggesting that, despite their size, these fragments were not products of aggrecanase cleavage in the interglobular domain. ADAMTS-5, but not ADAMTS-1, -4, or -9, was up-regulated 8-fold by retinoic acid and 17-fold by IL-1␣ treatment. The data show that whereas ADAMTS-5 is entirely responsible for cleavage in the interglobular domain, cleavage in the chondroitin sulfate-rich region is driven either by ADAMTS-4, which compensates for loss of ADAMTS-5 in this experimental system, or possibly by another aggrecanase. The data show that there are differential aggrecanase activities with preferences for separate regions of the core protein.A feature of joint pathology in arthritis is destruction of articular cartilage. The major structural components of cartilage are type II collagen and the large aggregating proteoglycan, aggrecan. In healthy cartilage, type II collagen and aggrecan confer strength and compliance that enables this tissue to resist compressive forces. In arthritic diseases, the progressive degradation of aggrecan and type II collagen leads to cartilage erosion. Aggrecan has two globular domains, G1 and G2 at the N terminus, and a third globular domain, G3 at the C terminus. An extended sequence between the G2 and G3 domains is heavily substituted with keratan sulfate and chondroitin sulfate chains, organized into a distinct keratan sulfate-rich region and chondroitin sulfate-1 (CS-1) 2 and chondroitin sulfate-2 (CS-2) domains. An interglobular domain (IGD) of ϳ150 amino acids separates G1 from G2.The aggrecan IGD is highly sensitive to proteinases. Proteolysis in the IGD releases the entire chondroitin sulfate and keratan sulfate-rich regions essential for the biomechanical properties of aggrecan, and is therefore thought to be the most detrimental for cartilage function. In pathology, proteolysis is driven mainly by aggrecanases...

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Section: Discussionmentioning

confidence: 82%

ADAMTS-5 Deficiency Does Not Block Aggrecanolysis at Preferred Cleavage Sites in the Chondroitin Sulfate-rich Region of Aggrecan

East

Stanton

Golub

et al. 2007

Journal of Biological Chemistry

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“…T-2 toxin may dissociate and free HA from aggregating aggrecan, seriously damage aggrecan biological functions, initiate aggrecan degradation process and eventually lead to cartilage degradation. While its biochemical and molecular biological mechanism is not clear to date, previous study indicated that the increasing aggrecanase level in cartilage may be involved (Chockalingam et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Promotion of the articular cartilage proteoglycan degradation by T-2 toxin and selenium protective effect

Liu

Cao

Shi

et al. 2008

J. Zhejiang Univ. Sci. B

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Abstract:Objective: To identify the relationship between T-2 toxin and Kashin-Beck disease (KBD), the effects of T-2 toxin on aggrecan metabolism in human chondrocytes and cartilage were investigated in vitro. Methods: Chondrocytes were isolated from human articular cartilage and cultured in vitro. Hyaluronic acid (HA), soluble CD44 (sCD44), IL-1β and TNF-α levels in supernatants were measured by enzyme-linked immunosorbent assay (ELISA). CD44 content in chondrocyte membrane was determined by flow cytometry (FCM). CD44, hyaluronic acid synthetase-2 (HAS-2) and aggrecanases mRNA levels in chondrocytes were determined using reverse transcription polymerase chain reaction (RT-PCR). Immunocytochemical method was used to investigate expressions of BC-13, 3-B-3(−) and 2-B-6 epitopes in the cartilage reconstructed in vitro. Results: T-2 toxin inhibited CD44, HAS-2, and aggrecan mRNA expressions, but promoted aggrecanase-2 mRNA expression. Meanwhile, CD44 expression was found to be the lowest in the chondrocytes cultured with T-2 toxin and the highest in control plus selenium group. In addition, ELISA results indicated that there were higher sCD44, IL-1β and TNF-α levels in T-2 toxin group. Similarly, higher HA levels were also observed in T-2 toxin group using radioimmunoprecipitation assay (RIPA). Furthermore, using monoclonal antibodies BC-13, 3-B-3 and 2-B-6, strong positive immunostaining was found in the reconstructed cartilage cultured with T-2 toxin, whereas no positive staining or very weak staining was observed in the cartilage cultured without T-2 toxin. Selenium could partly inhibit the effects of T-2 toxin above. Conclusion: T-2 toxin could inhibit aggrecan synthesis, promote aggrecanases and pro-inflammatory cytokines production, and consequently induce aggrecan degradation in chondrocytes. These will perturb metabolism balance between aggrecan synthesis and degradation in cartilage, inducing aggrecan loss in the end, which may be the initiation of the cartilage degradation.

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“…Of these, ADAMTS4 and 5 exhibit the most powerful aggrecanase activities Tortorella et al, 1999Tortorella et al, , 2001Rogerson et al, 2008). ADAMTSs and the MMPs reportedly play important roles in the metabolism in the extracellular matrix of the cartilage during the development and the progress of joint diseases (Martel-Pelletier et al, 2001;Arner et al, 2002;Chockalingam et al, 2004;Pásztói et al, 2009). Although ADAMTSs are especially believed to be involved in the cellular growth, differentiation, and maturation of the growth plate chondrocytes, their roles in the endochondral ossification have not been completely elucidated (Demircan et al, 2005;Mitani et al, 2006;Hatipoglu et al, 2009a;Yaykasli et al, 2009).…”

Section: Immunohistochemistrymentioning

confidence: 99%

A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9) expression by chondrocytes during endochondral ossification

Kumagishi

Nishida

Yamaai

et al. 2009

Arch. Histol. Cytol.

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chondrocyte phenotypes, respectively. We found the gene expression of ADAMTS9 by ATDC5 cells as a dual mode, both before the expression of type X collagen and after hypertrophic differentiation. The immunoreactivity of ADAMTS9 was observed in chondrocytes of proliferative a n d h y p e r t r o p h i c z o n e s i n t h e g r o w t h p l a t e . T h e population of ADAMTS9 positive cells decreased with age. The results of the present study suggest that ADAMTS9 might have a role in aggrecan cleavage around the chondrocytes to allow chondrocyte proliferation and hypertrophy.

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Release of hyaluronan and hyaladherins (aggrecan G1 domain and link proteins) from articular cartilage exposed to ADAMTS‐4 (aggrecanase 1) or ADAMTS‐5 (aggrecanase 2)

Cited by 47 publications

References 57 publications

ADAMTS-5 Deficiency Does Not Block Aggrecanolysis at Preferred Cleavage Sites in the Chondroitin Sulfate-rich Region of Aggrecan

ADAMTS-5 Deficiency Does Not Block Aggrecanolysis at Preferred Cleavage Sites in the Chondroitin Sulfate-rich Region of Aggrecan

Promotion of the articular cartilage proteoglycan degradation by T-2 toxin and selenium protective effect

A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9) expression by chondrocytes during endochondral ossification

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