Sulfated Glycosaminoglycans Control the Extracellular Trafficking and the Activity of the Metalloprotease Inhibitor TIMP-3

Troeberg, Linda; Lazenbatt, Christopher; Anower-E-Khuda, Md. Ferdous; Freeman, Craig; Federov, Oleg; Habuchi, Hiroko; Habuchi, Osami; Kimata, Koji; Nagase, Hideaki

doi:10.1016/j.chembiol.2014.07.014

Cited by 68 publications

(70 citation statements)

References 52 publications

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“…This is provided by an sHA1-induced pronounced increase of different MMP inhibitors to decrease the overall ECM degradation. Among those, TIMP3, which is the only one among four TIMPs that is tightly anchored in the pericellular matrix, interacts with sulfated GAG as shown for heparin and chondroitin sulfate (79,80). As shown before, after sHA1 exposition most prominent regulated proteins were found in biological function of cell-matrix interaction, ECM organization, and regulation of growth factor bioavailability (Fig.…”

Section: Comparison Of the Matrix Vesicle Proteome With Hbmsc Proteomementioning

confidence: 64%

Osteoblast-released Matrix Vesicles, Regulation of Activity and Composition by Sulfated and Non-sulfated Glycosaminoglycans

Schmidt

Kliemt

Preissler

et al. 2016

Molecular & Cellular Proteomics

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Our aging population has to deal with the increasing threat of age-related diseases that impair bone healing. One promising therapeutic approach involves the coating of implants with modified glycosaminoglycans (GAGs) that mimic the native bone environment and actively facilitate skeletogenesis. In previous studies, we reported that coatings containing GAGs, such as hyaluronic acid (HA) and its synthetically sulfated derivative (sHA1) as well as the naturally low-sulfated GAG chondroitin sulfate (CS1), reduce the activity of bone-resorbing osteoclasts, but they also induce functions of the bone-forming cells, the osteoblasts. However, it remained open whether GAGs influence the osteoblasts alone or whether they also directly affect the formation, composition, activity, and distribution of osteoblast-released matrix vesicles (MV), which are supposed to be the active machinery for bone formation. Here, we studied the molecular effects of sHA1, HA, and CS1 on MV activity and on the distribution of marker proteins. Furthermore, we used comparative proteomic methods to study the relative protein compositions of isolated MVs and MV-releasing osteoblasts. The MV proteome is much more strongly regulated by GAGs than the cellular proteome. GAGs, especially sHA1, were found to severely impact vesicle-extracellular matrix interaction and matrix vesicle activity, leading to stronger extracellular matrix formation and mineralization. This

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Section: Comparison Of the Matrix Vesicle Proteome With Hbmsc Proteomementioning

confidence: 64%

Osteoblast-released Matrix Vesicles, Regulation of Activity and Composition by Sulfated and Non-sulfated Glycosaminoglycans

Schmidt

Kliemt

Preissler

et al. 2016

Molecular & Cellular Proteomics

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“…2). In this regard, Troeberg et al [49] reported that endocytic removal of TIMP-3 was inhibited by heparin, heparan sulfate proteoglycans and chondroitin sulfate E, making TIMP-3 available for metalloproteinase inhibition. In addition, the sulfated GAG-TIMP-3 complex has higher affinity for ADAMTS-4 and ADAMTS-5 than TIMP-3 alone, but the sulfation pattern of the GAG is crucial for this activity.…”

Section: Ectodomain Shedding Of Lrp1mentioning

confidence: 97%

“…GAGs increase TIMP-3 affinity for MMP-2, − 7 [46], ADAMTS-2 [47], ADAMTS-4 and ADAMTS-5 [48], and this is likely to be the case for other sulfated GAG-binding metalloproteinases. Notably, the ability of sulfated GAGs to increase the affinity between TIMP-3 and ADAMTS-4 and ADAMTS-5 is highly dependent on the sulfation pattern of the GAG [49].…”

Section: Regulation By Locationmentioning

confidence: 99%

Extracellular regulation of metalloproteinases

2015

Self Cite

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Matrix metalloproteinases (MMPs) and adamalysin-like metalloproteinase with thrombospondin motifs (ADAMTSs) belong to the metzincin superfamily of metalloproteinases and they play key roles in extracellular matrix catabolism, activation and inactivation of cytokines, chemokines, growth factors, and other proteinases at the cell surface and within the extracellular matrix. Their activities are tightly regulated in a number of ways, such as transcriptional regulation, proteolytic activation and interaction with tissue inhibitors of metalloproteinases (TIMPs). Here, we highlight recent studies that have illustrated novel mechanisms regulating the extracellular activity of these enzymes. These include allosteric activation of metalloproteinases by molecules that bind outside the active site, modulation of location and activity by interaction with cell surface and extracellular matrix molecules, and endocytic clearance from the extracellular milieu by low-density lipoprotein receptor-related protein 1 (LRP1).

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“…13 Little free TIMP-3 is present in tissues since it binds tightly to sulfated oligosaccharides in the ECM and is also endocytosed by cells after it has been secreted. 16,17 Hyaluronic acid hydrogel was used to encapsulate recombinant human TIMP-3, to which it binds through electrostatic interactions, allowing slow release in vivo. In pigs, MI was induced by coronary ligation, and the hydrogel/ TIMP-3, hydrogel alone, or saline was injected into the MI region in subgroups.…”

Section: 15mentioning

confidence: 99%

Hypothesis

Lizotte-Waniewski

Brew

Hennekens

2015

J Cardiovasc Pharmacol Ther

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The hypothesis that matrix metalloproteinase (MMP) inhibitors reduce risks of cardiovascular disease in humans is plausible, unproven, and difficult to test, due, in part, to differences in specificity and route of administration. Endogenous tissue inhibitors of metalloproteinases (TIMPs) are tight-binding, protein inhibitors that function in vivo and can be engineered to enhance specificity for desired targets. Nonetheless, TIMPs have been difficult to test, in part, because their secondary functions, including cell growth promotion and angiogenesis, raise concerns about side effects and they cannot be delivered orally. In contrast, doxycycline and other chemically modified tetracyclines are broad-spectrum, reversible MMP inhibitors with lower affinity but can be taken orally and have US Food and Drug Administration approval. The completed phase 2 randomized trials in humans of MMP inhibitors have methodologic limitations but generally show no significant benefits with adverse effects. At present, the principal research challenge is to achieve a better understanding of the complexities of biological functions of MMPs and subsequently to conduct large-scale phase 3 trials.

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Sulfated Glycosaminoglycans Control the Extracellular Trafficking and the Activity of the Metalloprotease Inhibitor TIMP-3

Cited by 68 publications

References 52 publications

Osteoblast-released Matrix Vesicles, Regulation of Activity and Composition by Sulfated and Non-sulfated Glycosaminoglycans

Osteoblast-released Matrix Vesicles, Regulation of Activity and Composition by Sulfated and Non-sulfated Glycosaminoglycans

Extracellular regulation of metalloproteinases

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