Review
Matrix metalloproteinase 12 silencing: A therapeutic approach to treat pathological lung tissue remodeling?

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Abstract

Among the large matrix metalloproteinases (MMPs) family, MMP-12, also referred to as macrophage elastase, plays a significant role in chronic pulmonary pathologies characterized by an intense tissue remodeling such as asthma and COPD. This review will summarize knowledge about MMP-12 structure, functions and mechanisms of activation and regulation, including potential MMP-12 modulation by microRNA. As MMP-12 is involved in many tissue remodeling diseases, efforts have been made to develop specific synthetic inhibitors. However, at this time, very few chemical inhibitors have proved to be efficient and specific to a particular MMP. The relevance of silencing MMP-12 by RNA interference is highlighted. The specificity of this approach using siRNA or shRNA and the strategies to deliver these molecules in the lung are discussed.

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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