ReviewMatrix metalloproteinase 12 silencing: A therapeutic approach to treat pathological lung tissue remodeling?
Section snippets
Tissue remodeling in lung disease
Matrix metalloproteinases (MMPs) are believed to be the main physiological mediators of extracellular matrix macromolecule degradation and to be the initiators of tissue remodeling. These enzymes play a pivotal role in tissue remodeling during physiological processes such as embryonic development, morphogenesis, post-natal development and during pathological conditions [1].
MMPs comprise a family of 25 related, yet distinct, zinc-containing enzymes [2]. Collectively, they are able to degrade all
Brief overview of MMP-12 structure and function
Human MMP-12 is translated as a 1.8 kb transcript encoding a 470 amino-acid proenzyme that is 64% identical to the mouse protein [31]. Its molecular mass is 54 kDa and comprises three domains (Fig. 2).
A 9 kDa amino-terminal propeptide domain I (following a short signaling peptide) includes a highly conserved cysteine residue where the thiol interacts with the zinc ion in the proenzyme form: this interaction is involved in the maintenance of enzyme latency.
Domain II or catalytic domain (22 kDa)
Regulation of MMP-12 expression and activation in the lung
Gene expression can be regulated during various steps leading from DNA to mRNA and finally to protein. These regulations can occur at a transcriptional level (control of RNA transcription), at a post-transcriptional level (control of mRNA maturation, stabilization or degradation, splicing, transport and/or localization), at a translational level (control of ribosomal translation of mRNA to protein), at a post-translational level (glycosylation, control of protein activity, degradation, storage,
Most efficient MMP-12 chemical inhibitors
Since MMP-12 is not only involved in lung tissue remodeling-associated diseases [35], [37], [41], [46], [50], [81], [82], [83], [84], [85], [86], [87], [88], [89], substantial efforts have been made to develop MMP-12 synthetic inhibitors. However, inhibiting a specific MMP is a difficult goal because of the high conservation between many MMPs in terms of overall 3D-structure, topology of the catalytic domain and requirement of specific amino-acid residues in the active site [90], [91]. This is
Why to choose siRNA silencing of MMP-12?
As reviewed above, the pharmacological use of MMPs inhibitors has been largely hampered by their lack of specificity. Moreover, molecules that were tested in clinical trials have failed to prove any beneficial effect while they were associated with a severe side effect consisting in a musculoskeletal syndrome mainly manifesting as pain and immobility of most joints [102]. This may be due to unspecific inhibition of the other MMPs but also of members of other families of metalloproteinases such
Conclusion
Lung disorders represent a good model for RNA interference therapy development because local administration of siRNA may be easier to achieve than systemic administration. Pulmonary fibrosis, that is characterized by an increase in the expression of extracellular matrix enzyme and protein mRNA and protein such as MMP-12, is not yet successfully treated. Inhibition or degradation of the corresponding mRNA should be a solution to reduce the development of the associated diseases. However,
Competing interests
The author(s) declare that they have no competing interests.
Acknowledgements
We gratefully thank Professor Betty Nusgens (GIGA-Research, Laboratory of Connective Tissues Biology, University of Liège, Belgium) for her helpful suggestions during the preparation of this manuscript.
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2017, European Journal of PharmacologyCitation Excerpt :The dysregulated action of MMPs implicated in IPF play a central role in the disease pathogenesis (Dancer et al., 2011). As suggested by our data, inhibiting MMPs in IPF may, therefore, have therapeutic potential (Garbacki et al., 2009; Pottier et al., 2007). In complement to MRI, noninvasive monitoring of pulmonary fibrosis by targeting MMPs with fluorescent probes (Cai et al., 2013) may prove useful when testing MMP inhibitors in vivo in the BLM model.
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2014, Journal of Pharmaceutical and Biomedical AnalysisCitation Excerpt :This protein may be critical to the maintenance of tissue homeostasis by suppressing the proliferation of quiescent tissues in response to angiogenic factors, and by inhibiting protease activity in tissues undergoing remodeling of the extracellular matrix. It is also related to disorganization of lung parenchyma [43]. Levels of pigment epithelium-derived factor (PEDF; SERPINF1) were found significantly different between NSCLC patients and benign-disease controls (pneumonia, tuberculosis), both in the pleural effusion and the serum samples [44].
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2013, Toxicology and Applied PharmacologySynthesis of two new alkyne-bearing linkers used for the preparation of siRNA for labeling by click chemistry with fluorine-18
2012, Applied Radiation and IsotopesCitation Excerpt :The sense-strand and the antisense-strand of the siRNA were synthesized with modified alkyne solid support 10 and a normal solid support, respectively, and finally annealed according to Mercier et al. (2011). The following oligonucleotide sequences (synthesized by Eurogentec) were used: 5-UCACUUACAGGAUCUAUAA-3 (sense) and 5-UUAUAGAUCCUGUAAGUGA-3 (antisense)(Garbacki et al., 2009). The modified siRNA 23 was clicked with 1-(azidomethyl)-4-fluorobenzene [19F]24 (Demko and Sharpless, 2002).