Glycosaminoglycans Influence Enzyme Activity of MMP2 and MMP2/TIMP3 Complex Formation - Insights at Cellular and Molecular Level

Overview

Journal Sci Rep

Specialty Science

Date 2019 Mar 22

PMID 30894640

Citations 16

Authors

Gloria Ruiz-Gomez

Sarah Vogel

Stephanie Moller

M Teresa Pisabarro

Ute Hempel

Affiliations

Soon will be listed here.

Abstract

The extracellular matrix (ECM) is a highly dynamic network constantly remodeled by a fine-tuned protein formation and degradation balance. Matrix metalloproteinases (MMPs) constitute key orchestrators of ECM degradation. Their activity is controlled by tissue inhibitors of metalloproteinases (TIMPs) and glycosaminoglycans (GAG). Here, we investigated the molecular interplay of MMP2 with different GAG (chondroitin sulfate, hyaluronan (HA), sulfated hyaluronan (SH) and heparin (HE)) and the impact of GAG on MMP2/TIMP3 complex formation using in vitro-experiments with human bone marrow stromal cells, in silico docking and molecular dynamics simulations. SH and HE influenced MMP2 and TIMP3 protein levels and MMP2 activity. Only SH supported the alignment of both proteins in fibrillar-like structures, which, based on our molecular models, would be due to a stabilization of the interactions between MMP2-hemopexin domain and TIMP3-C-terminal tail. Dependent on the temporal sequential order in which the final ternary complex was formed, our models indicated that SH and HA can affect TIMP3-induced MMP2 inhibition through precluding or supporting their interactions, respectively. Our combined experimental and theoretical approach provides valuable new insights on how GAG interfere with MMP2 activity and MMP2/TIMP3 complex formation. The results obtained evidence GAG as promising molecules for fine-balanced intervention of ECM remodeling.

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References

Hempel U, Matthaus C, Preissler C, Moller S, Hintze V, Dieter P . Artificial matrices with high-sulfated glycosaminoglycans and collagen are anti-inflammatory and pro-osteogenic for human mesenchymal stromal cells. J Cell Biochem. 2014; 115(9):1561-71. DOI: 10.1002/jcb.24814. View

Kunze R, Rosler M, Moller S, Schnabelrauch M, Riemer T, Hempel U . Sulfated hyaluronan derivatives reduce the proliferation rate of primary rat calvarial osteoblasts. Glycoconj J. 2009; 27(1):151-8. DOI: 10.1007/s10719-009-9270-9. View

Vogel S, Arnoldini S, Moller S, Schnabelrauch M, Hempel U . Sulfated hyaluronan alters fibronectin matrix assembly and promotes osteogenic differentiation of human bone marrow stromal cells. Sci Rep. 2016; 6:36418. PMC: 5093463. DOI: 10.1038/srep36418. View

Jouy F, Lohmann N, Wandel E, Ruiz-Gomez G, Pisabarro M, Beck-Sickinger A . Sulfated hyaluronan attenuates inflammatory signaling pathways in macrophages involving induction of antioxidants. Proteomics. 2017; 17(10):e1700082. DOI: 10.1002/pmic.201700082. View

Salbach J, Kliemt S, Rauner M, Rachner T, Goettsch C, Kalkhof S . The effect of the degree of sulfation of glycosaminoglycans on osteoclast function and signaling pathways. Biomaterials. 2012; 33(33):8418-29. DOI: 10.1016/j.biomaterials.2012.08.028. View

Buttner M, Moller S, Keller M, Huster D, Schiller J, Schnabelrauch M . Over-sulfated chondroitin sulfate derivatives induce osteogenic differentiation of hMSC independent of BMP-2 and TGF-β1 signalling. J Cell Physiol. 2012; 228(2):330-40. DOI: 10.1002/jcp.24135. View

Jha S, Kanaujia S, Limaye A . Direct inhibition of matrix metalloproteinase-2 (MMP-2) by (-)-epigallocatechin-3-gallate: A possible role for the fibronectin type II repeats. Gene. 2016; 593(1):126-130. DOI: 10.1016/j.gene.2016.07.061. View

Butler G, Apte S, Willenbrock F, Murphy G . Human tissue inhibitor of metalloproteinases 3 interacts with both the N- and C-terminal domains of gelatinases A and B. Regulation by polyanions. J Biol Chem. 1999; 274(16):10846-51. DOI: 10.1074/jbc.274.16.10846. View

Hempel U, Hintze V, Moller S, Schnabelrauch M, Scharnweber D, Dieter P . Artificial extracellular matrices composed of collagen I and sulfated hyaluronan with adsorbed transforming growth factor β1 promote collagen synthesis of human mesenchymal stromal cells. Acta Biomater. 2011; 8(2):659-66. DOI: 10.1016/j.actbio.2011.10.026. View

10.

Oswald J, Boxberger S, Jorgensen B, Feldmann S, Ehninger G, Bornhauser M . Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells. 2004; 22(3):377-84. DOI: 10.1634/stemcells.22-3-377. View

11.

Mosig R, Dowling O, DiFeo A, Ramirez M, Parker I, Abe E . Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth. Hum Mol Genet. 2007; 16(9):1113-23. PMC: 2576517. DOI: 10.1093/hmg/ddm060. View

12.

Morgunova E, Tuuttila A, Bergmann U, Tryggvason K . Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2. Proc Natl Acad Sci U S A. 2002; 99(11):7414-9. PMC: 124245. DOI: 10.1073/pnas.102185399. View

13.

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View

14.

Schmidt J, Vogel S, Moeller S, Kalkhof S, Schubert K, von Bergen M . Sulfated hyaluronic acid and dexamethasone possess a synergistic potential in the differentiation of osteoblasts from human bone marrow stromal cells. J Cell Biochem. 2018; 120(5):8706-8722. DOI: 10.1002/jcb.28158. View

15.

Etique N, Verzeaux L, Dedieu S, Emonard H . LRP-1: a checkpoint for the extracellular matrix proteolysis. Biomed Res Int. 2013; 2013:152163. PMC: 3723059. DOI: 10.1155/2013/152163. View

16.

Isnard N, Robert L, Renard G . Effect of sulfated GAGs on the expression and activation of MMP-2 and MMP-9 in corneal and dermal explant cultures. Cell Biol Int. 2003; 27(9):779-84. DOI: 10.1016/s1065-6995(03)00167-7. View

17.

Hempel U, Moller S, Noack C, Hintze V, Scharnweber D, Schnabelrauch M . Sulfated hyaluronan/collagen I matrices enhance the osteogenic differentiation of human mesenchymal stromal cells in vitro even in the absence of dexamethasone. Acta Biomater. 2012; 8(11):4064-72. DOI: 10.1016/j.actbio.2012.06.039. View

18.

Arpino V, Brock M, Gill S . The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix Biol. 2015; 44-46:247-54. DOI: 10.1016/j.matbio.2015.03.005. View

19.

Worley J, Thompkins P, Lee M, Hutton M, Soloway P, Edwards D . Sequence motifs of tissue inhibitor of metalloproteinases 2 (TIMP-2) determining progelatinase A (proMMP-2) binding and activation by membrane-type metalloproteinase 1 (MT1-MMP). Biochem J. 2003; 372(Pt 3):799-809. PMC: 1223438. DOI: 10.1042/BJ20021573. View

20.

Salbach-Hirsch J, Ziegler N, Thiele S, Moeller S, Schnabelrauch M, Hintze V . Sulfated glycosaminoglycans support osteoblast functions and concurrently suppress osteoclasts. J Cell Biochem. 2013; 115(6):1101-11. DOI: 10.1002/jcb.24750. View