Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions

Abstract

Matrix metalloproteinases (MMPs) are a diverse group of proteolytic enzymes and play an important role in the degradation and remodeling of the extracellular matrix (ECM). In normal physiological conditions, MMPs are usually minimally expressed. Despite their low expression, MMPs have been implicated in many cellular processes ranging from embryological development to apoptosis. The activity of MMPs is controlled at three different stages: (1) transcription; (2) zymogen activation; and (3) inhibition of active forms by tissue inhibitor metalloproteinases (TIMPs). They can collectively degrade any component of ECM and basement membrane, and their excessive activity has been linked to numerous pathologies mainly including, but not limited to, tumor invasion and metastasis. The lack of information about several MMPs and the steady stream of new discoveries suggest that there is much more to be studied in this field. In particular, there is a need for controlling their expression in disease states. Various studies over the past 30 years have found that each MMP has a specific mode of activation, action, and inhibition. Drugs specifically targeting individual MMPs could revolutionize the treatment of a great number of health conditions and tremendously reduce their burden. In this review article, we have summarized the recent advances in understanding the role of MMPs in physiological and pathological conditions. J. Cell. Physiol. 231: 2599-2621, 2016. © 2016 Wiley Periodicals, Inc.

Secreted tissue inhibitor of matrix metalloproteinase restricts trans-synaptic signaling to coordinate synaptogenesis

“…1). This local regulation of Mmp functional dynamics has not been reported to our knowledge in neuronal synapses, but is consistent with known roles of Timp in non-neuronal contexts (Kessenbrock et al, 2010;Mittal et al, 2016). We find that postsynaptic Timp limits presynaptic NMJ architecture and bouton formation (Fig.…”

Horizontal gene transfer in the sponge Amphimedon queenslandica

“…The aspzincins belong in the metallopeptidase superfamily, which also contains the large matrix metalloproteinase (MMP) family that remodels and degrades the extracellular matrix (ECM) in animals (Ra and Parks 2007;Mittal et al 2016). This metallopeptidase activity of MMPs is vital for proper ECM remodelling, which in turn is imperative for correct ECM functioning, including the roles of the ECM in signalling pathways governing the growth and differentiation of cells (Lukashev and Werb 1998;Ra and Parks 2007;Mittal et al 2016).…”

“…This metallopeptidase activity of MMPs is vital for proper ECM remodelling, which in turn is imperative for correct ECM functioning, including the roles of the ECM in signalling pathways governing the growth and differentiation of cells (Lukashev and Werb 1998;Ra and Parks 2007;Mittal et al 2016). It has therefore been speculated that perhaps some of the aspzincins contribute to ECM remodelling in sponges , and this is explored further below.…”

“…Aspzincins belong in the large metallopeptidase superfamily, which also contains the matrix metalloproteinase family that remodels and degrades the ECM, including collagen, in animals (Ra and Parks 2007;Mittal et al 2016). Therefore, the expression of the AqAspzScs in sclerocytes along with silicatein suggests not just the co-option of some AqAspzs for a role in spiculogenesis, but prompts further speculation that this role could be involved in the reconstruction of the collagen that promotes correct spicule development.…”

“…These genes are enriched with transmembrane and cell surface domains, namely cadherins (function in cell-adhesion; Takeichi 1988), SRCRs (function in nonself-recognition, immunity, host-microbiome interactions; Blumbach et al 1998;Steindler et al 2007;Hentshel et al 2012;Buckley and Rast 2015;Fieth et al 2016) and TIGs (function in ECM dissociation and movement; Collesi et al 1996). Along with the typical MMP ECM remodelling role of hemopexin domains (Ra and Parks 2007;Mittal et al 2016), the described putative co-expression of the aspzincin-hemopexin gene with these extracellular genes supports speculation that the sponge aspzincin-hemopexin genes have a role in ECM remodelling.…”