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Modulation of Systemic Metabolism by MMP‐2: From MMP‐2 Deficiency in Mice to MMP‐2 Deficiency in Patients

Carlos Fernandez‐Patron, Zamaneh Kassiri, Dickson Leung

10.1002/cphy.c160010

Source: Volume 6, Issue 4, October 2016

Published online: September 2016

Full Article on Wiley Online Library



ABSTRACT

Matrix metalloproteinase‐2 (MMP‐2) is a 72‐kDa zinc‐ and calcium‐dependent endopeptidase with intracellular and extracellular functions ranging from the modulation of extracellular matrix remodeling to cell growth and migration, angiogenesis, inflammation, and metabolism. An upregulation of MMP‐2 activity has the potential to deregulate lipid metabolism through the cleavage of numerous metabolic mediators including plasma lipoproteins and cell surface receptors of lipoproteins. Paradoxically, MMP‐2 deficiency induces inflammation and deregulates metabolism. Humans and mice with a deficiency in MMP‐2 activity share a complex metabolic and inflammatory syndrome including cardiac dysfunction associated with congenital heart defects (in humans) and metabolic disorder (mice), arthritis, loss of bone mass, lipodystrophy, and delayed growth. The etiology of the inflammatory and metabolic syndrome in MMP‐2 deficiency is unknown and there is currently no cure for MMP‐2 deficiency in patients. Recent research suggests that the pathophysiology of MMP‐2 deficiency in mice and humans is influenced by a heart‐centric endocrine mechanism signaled by a cardiac‐specific secreted phospholipase A2 (cardiac sPLA2), which is released from cardiomyocytes in response to monocyte chemoattractant protein‐3, a proinflammatory cytokine normally cleaved and inactivated by MMP‐2. This review summarizes many important proteolytic functions of MMP‐2 and recapitulates recent reports linking the heart to systemic metabolic control through the MMP‐2/cardiac sPLA2 axis. The authors suggest that MMP‐2 deficiency should, perhaps, be viewed and treated as an endocrine condition of excess sPLA2, a concept with particular importance for the therapeutic treatment of MMP‐2‐deficient patients. The possible existence of tissue‐specific MMP/cytokine/PLA2 signaling systems is discussed. © 2016 American Physiological Society. Compr Physiol 6:1935‐1949, 2016.

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Figure 1. Figure 1. Members of the MMP family share a largely conserved domain structure (37,72,114).
Figure 2. Figure 2. (A) Linear structure and domain organization of MMP‐2. (B) The catalytic activity of MMP‐2 (72 kDa) is strongly regulated by its propeptide domain (139). A cysteine residue within the propeptide domain binds to the Zn2+ atom in the catalytic domain inhibiting substrate binding and proteolysis. Oxidative stress and proteolysis are two mechanisms of MMP‐2 activation. S‐gluthathiolation is induced by oxidative stress. Purportedly, peroxynitrite (ONOO−) reacts with celullar GSH and a critical cysteine residue in the conserved region (PRCGVPD) of the propeptide domain. The S‐gluthathiolated cysteine no longer can complex with the Zn2+ atom in the catalytic domain. The resultant enzyme (72 kDa) is active despite containing the propeptide domain. Proteolytic removal of the propeptide domain [e.g., by MMP‐14, and coagulation cascade proteases such as thrombin (42,167) and plasmin (6,9,108)] is a major mechanism yielding catalytically active MMP‐2 (64 kDa).
Figure 3. Figure 3. Endocrine model of metabolic and inflammatory syndrome in MMP‐2 deficiency. (A) In normal physiology, MMP‐2 is anti‐inflammatory by cleaving and inactivating proinflammatory cytokines, such as monocyte chemoattractant protein‐3 (MCP‐3) (102,103). MMP‐2 deficiency results in an excess of cardiac MCP‐3, which promotes the release of active cardiac sPLA2 from myocardium (57). The release of cardiac sPLA2 from myocardium is governed by MMP‐2 and may enable the heart to exert important endocrine functions such as regulation of metabolism and inflammation in target organs including the heart, liver, adipose tissue bones, and skeletal muscle. (B) MMP‐2 deficiency causes similar problems in humans and mice, which could be explained as an excess of cardiac sPLA2. (C) The proinflammatory activity of cardiac sPLA2 is kept in balance by the anti‐inflammatory activity of MMP‐2, which prevents cardiac sPLA2 release from myocardium. Studies with mice suggest that MMP‐2 gene mutations and polymorphisms as well as drugs with MMP inhibitory actions may inhibit MMP‐2 catalytic activity inducing a state of MMP‐2 deficiency where inflammation is promoted, at least in part, by the relative excess of cardiac sPLA2 activity versus MMP‐2 activity (17,57). It is thus suggested that treatment of metabolic and inflammatory syndrome in MMP‐2‐deficient patients should be directed to inhibiting sPLA2 activity. An alternative would be gene editing to correct the MMP‐2 gene defect in patients such that MMP‐2 activity (and consequently, cardiac sPLA2 activity) are restored to normal levels.
Figure 4. Figure 4. Proposed heart‐centric endocrine metabolic circuits mediated by cardiac secreted PLA2 and governed by MMP‐2. The heart is thought to be a major source of cardiac sPLA2, whose release is stimulated by MCP‐3, a chemokine normally cleaved and converted into a chemokine receptor antagonist by MMP‐2. Cardiac sPLA2 circulates in the plasma and may thus reach distant target organs affecting their inflammatory and lipid metabolic phenotype. An endocrine function of the heart is to release cardiac sPLA2, which signals to the liver to provide the heart with triglycerides in the form of VLDL. Other factors released from noncardiac target organs (indicated by “?” in the diagram) could also influence the metabolism of the heart.


Figure 1. Members of the MMP family share a largely conserved domain structure (37,72,114).


Figure 2. (A) Linear structure and domain organization of MMP‐2. (B) The catalytic activity of MMP‐2 (72 kDa) is strongly regulated by its propeptide domain (139). A cysteine residue within the propeptide domain binds to the Zn2+ atom in the catalytic domain inhibiting substrate binding and proteolysis. Oxidative stress and proteolysis are two mechanisms of MMP‐2 activation. S‐gluthathiolation is induced by oxidative stress. Purportedly, peroxynitrite (ONOO−) reacts with celullar GSH and a critical cysteine residue in the conserved region (PRCGVPD) of the propeptide domain. The S‐gluthathiolated cysteine no longer can complex with the Zn2+ atom in the catalytic domain. The resultant enzyme (72 kDa) is active despite containing the propeptide domain. Proteolytic removal of the propeptide domain [e.g., by MMP‐14, and coagulation cascade proteases such as thrombin (42,167) and plasmin (6,9,108)] is a major mechanism yielding catalytically active MMP‐2 (64 kDa).


Figure 3. Endocrine model of metabolic and inflammatory syndrome in MMP‐2 deficiency. (A) In normal physiology, MMP‐2 is anti‐inflammatory by cleaving and inactivating proinflammatory cytokines, such as monocyte chemoattractant protein‐3 (MCP‐3) (102,103). MMP‐2 deficiency results in an excess of cardiac MCP‐3, which promotes the release of active cardiac sPLA2 from myocardium (57). The release of cardiac sPLA2 from myocardium is governed by MMP‐2 and may enable the heart to exert important endocrine functions such as regulation of metabolism and inflammation in target organs including the heart, liver, adipose tissue bones, and skeletal muscle. (B) MMP‐2 deficiency causes similar problems in humans and mice, which could be explained as an excess of cardiac sPLA2. (C) The proinflammatory activity of cardiac sPLA2 is kept in balance by the anti‐inflammatory activity of MMP‐2, which prevents cardiac sPLA2 release from myocardium. Studies with mice suggest that MMP‐2 gene mutations and polymorphisms as well as drugs with MMP inhibitory actions may inhibit MMP‐2 catalytic activity inducing a state of MMP‐2 deficiency where inflammation is promoted, at least in part, by the relative excess of cardiac sPLA2 activity versus MMP‐2 activity (17,57). It is thus suggested that treatment of metabolic and inflammatory syndrome in MMP‐2‐deficient patients should be directed to inhibiting sPLA2 activity. An alternative would be gene editing to correct the MMP‐2 gene defect in patients such that MMP‐2 activity (and consequently, cardiac sPLA2 activity) are restored to normal levels.


Figure 4. Proposed heart‐centric endocrine metabolic circuits mediated by cardiac secreted PLA2 and governed by MMP‐2. The heart is thought to be a major source of cardiac sPLA2, whose release is stimulated by MCP‐3, a chemokine normally cleaved and converted into a chemokine receptor antagonist by MMP‐2. Cardiac sPLA2 circulates in the plasma and may thus reach distant target organs affecting their inflammatory and lipid metabolic phenotype. An endocrine function of the heart is to release cardiac sPLA2, which signals to the liver to provide the heart with triglycerides in the form of VLDL. Other factors released from noncardiac target organs (indicated by “?” in the diagram) could also influence the metabolism of the heart.
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Article Title: Modulation of Systemic Metabolism by MMP‐2: From MMP‐2 Deficiency in Mice to MMP‐2 Deficiency in Patients
 

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Carlos Fernandez‐Patron, Zamaneh Kassiri, Dickson Leung. Modulation of Systemic Metabolism by MMP‐2: From MMP‐2 Deficiency in Mice to MMP‐2 Deficiency in Patients. Compr Physiol 2016, 6: 1935-1949. doi: 10.1002/cphy.c160010