Editorial
Targeting matrix metalloproteinases in disease conditions Michele M Castro, Jose E Tanus-Santos Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil Correspondence to Professor Jose E Tanus-Santos, Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP 14049-900, Brazil; [email protected]; [email protected] Accepted 18 August 2014 Published Online First 5 September 2014
▸ http://dx.doi.org/10.1136/ acupmed-2014-010612
To cite: Castro MM, TanusSantos JE. Acupunct Med 2014;32:373–375.
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that are specialised to degrade extracellular protein assemblies which provide cells with much of the structural and biochemical apparatus. The members of this structure-related family of proteases, comprising more than 25 members, differ from each other, particularly in their location in the cell and the specificity of substrate proteolysis. The gelatinases, referred to as MMP-2 and MMP-9, are the main contributors to many cardiovascular diseases.1 For example, by degrading extracellular proteins such as collagen and elastin, MMP-2 triggers proliferation and migration of many cell types, thus favouring conditions ranging from angiogenesis and embryogenesis to hypertension, aortic aneurysm, inflammation and cancer.2 To protect MMPs from abnormal autoproteolysis or uncontrolled tissue degradation, MMPs are synthesised with an autoinhibitory propeptide which binds its cysteine thiol to the zinc ion in the catalytic domain. As soon as MMPs are secreted from cells the cysteine–zinc bond is disrupted by other proteases or by oxidising compounds, setting free the catalytic domain.1 Tissue inhibitors of MMPs (TIMPs) are the main inhibitors of MMP activity and bind to the catalytic site of MMPs non-covalently in a 1:1 stoichiometric ratio. Among four TIMPs, TIMP-2 binds preferentially to MMP-2 while TIMP-1 binds to MMP-9.1 In fact, increased MMP-9 and MMP-2 activities have been implicated in many inflammatory and degenerative brain diseases such as Alzheimer’s disease, multiple sclerosis, stroke and migraine. They may degrade proteins of the basement membrane in the brain vasculature, thus impairing the blood–brain barrier and favouring the influx of inflammatory cells and cytokines (figure 1), disrupting myelin.3 Although migraine is a common neurovascular disorder, its precise pathophysiology is not fully understood. Many studies
Castro MM, et al. Acupunct Med 2014;32:373–375. doi:10.1136/acupmed-2014-010649
suggest increased cortical activity (cortical spreading depression) which may cause blood–brain barrier destabilisation, meningeal inflammation and abnormal activation of nociceptors in the trigeminal nucleus.4 As MMPs may disrupt the blood–brain barrier in many neurological diseases, they are increasingly considered as potential targets in migraine (figure 1). In this respect, an increased plasma MMP-9/TIMP-1 ratio was shown in patients with migraine without aura compared with healthy controls.5 Other groups have also shown increased MMP-9 levels in the plasma of patients with migraine without aura during and between attacks.6 7 Increased MMP-9 release from inflammatory cells apparently disrupts the blood–brain barrier and contributes to cortical spreading depression-induced meningeal inflammation and migraine.8 Furthermore, we described for the first time increased plasma levels of MMP-2 and MMP-2/ TIMP-2 ratios in patients with migraine with and without aura.5 As MMP-2 is one of the main proteases involved in cardiovascular maladaptive changes in many diseases,2 higher levels of MMP-2 in patients with migraine may be a risk factor for the development of cardiovascular diseases. However, it is uncertain which mechanisms could be activated by MMP-2 to promote migraine. It is possible that MMP-2 cleaves the basement membrane of the surrounding vasculature, thus contributing to blood–brain barrier disruption, increased vascular permeability and inflammation. In this issue, Cayir et al9 examined the effects of acupuncture therapy on the circulating levels of MMP-2 in patients with migraine with and without aura. Acupuncture may exert anti-inflammatory effects10 and alleviate pain by stimulating the analgesic effects of some endogenous opioids. While the circulating MMP-2 levels were not modified by acupuncture, serum MMP-2 activity decreased 373
Editorial
Figure 1 Increased activity of matrix metalloproteinase-9 (MMP-9) and MMP-2 during migraine may degrade the basement membrane in the surrounding vasculature, thus disrupting the blood–brain barrier (BBB). It favours the influx of inflammatory cells to the brain, thus contributing to cortical spreading depression-induced meningeal inflammation and migraine. The mechanisms exerted by acupuncture to reduce inflammatory cell infiltration and migraine are not yet known. It is possible that acupuncture suppresses oxidative stress and then contributes to decrease MMP-9 and MMP-2 activity in the brain. Copyright Castro and Tanus-Santos.
significantly after the first and last session of acupuncture (total of 10) compared with baseline conditions. They also observed an amelioration in general health perception ( physical and mental) among the patients with migraine. While the mechanisms behind acupuncture-induced decreases in MMP-2 activity are uncertain, the authors speculated that the antiinflammatory effects exerted by acupuncture may contribute to lessen MMP-2 activity. It is also possible that acupuncture therapy may have suppressed oxidative stress by increasing the activity of antioxidant enzymes, as previously shown.10 Supporting this suggestion, attenuation of oxidative stress decreased MMP-2 activity very significantly.11 While Cayir et al9 have not measured TIMP-2 levels in their study, it is possible that acupuncture therapy may have increased TIMP-2 levels, thus decreasing MMP-2 activity without significantly changing MMP-2 levels. In addition, the genetic contribution to the variability in the responses found by Cayir et al has not been examined, and it is well known that genetic variations may affect the susceptibility of patients to develop diseases. Interestingly, MMP-2 polymorphisms and haplotypes ( particular combinations of genetic markers) may also affect circulating levels of MMP-2 and MMP-2/TIMP-2 ratios in patients with migraine.12 Moreover, a specific MMP-9 haplotype was associated with increased plasma MMP-9 concentrations in migraine patients, thus 374
predisposing them to the disease.13 It is therefore possible that therapies designed to mitigate MMP activity may be more efficient in some patients, particularly those predisposed to increased MMP levels. These issues remain to be studied in the context of the responses to acupuncture. The study by Cayir et al focused on serum MMP-2 levels. Further studies examining circulating MMP levels should take into consideration the fact that serum measurements are not appropriate for all MMPs, particularly MMP-9, because MMP-9 levels are artificially higher in serum than in plasma.14 In addition to using the appropriate samples and a control (sham) group, further studies should also take into consideration concomitant diseases and medications used by patients with migraine. These factors may significantly affect MMP concentrations and should be controlled for. Competing interests None. Provenance and peer review Not commissioned; internally peer reviewed.
REFERENCES 1 Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003;92:827–39. 2 Castro MM, Tanus-Santos JE. Inhibition of matrix metalloproteinases (MMPs) as a potential strategy to ameliorate
Castro MM, et al. Acupunct Med 2014;32:373–375. doi:10.1136/acupmed-2014-010649
Editorial
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4 5
6 7
8
9
hypertension-induced cardiovascular alterations. Curr Drug Targets 2013;14:335–43. Yong VW, Power C, Forsyth P, et al. Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci 2001;2:502–11. Silberstein SD. Migraine. Lancet 2004;363:381–91. Martins-Oliveira A, Speciali JG, Dach F, et al. Different circulating metalloproteinase profiles in women with migraine with and without aura. Clin Chim Acta 2009;408:60–4. Leira R, Sobrino T, Rodriguez-Yanez M, et al. MMP-9 immunoreactivity in acute migraine. Headache 2007;47:698–702. Imamura K, Takeshima T, Fusayasu E, et al. Increased plasma matrix metalloproteinase-9 levels in migraineurs. Headache 2008;48:135–9. Gursoy-Ozdemir Y, Qiu J, Matsuoka N, et al. Cortical spreading depression activates and upregulates MMP-9. J Clin Invest 2004;113:1447–55. Cayir Y, Ozdemir G, Celik M, et al. Acupuncture decreases matrix metalloproteinase-2 activity in migraine patients. Acupunct Med 2014;32:376–80.
Castro MM, et al. Acupunct Med 2014;32:373–375. doi:10.1136/acupmed-2014-010649
10 Leung MC, Yip KK, Ho YS, et al. Mechanisms underlying the effect of acupuncture on cognitive improvement: a systematic review of animal studies. J Neuroimmune Pharmacol 2014;9:492–507. 11 Castro MM, Rizzi E, Rodrigues GJ, et al. Antioxidant treatment reduces matrix metalloproteinase-2-induced vascular changes in renovascular hypertension. Free Radic Biol Med 2009;46:1298–307. 12 Goncalves FM, Martins-Oliveira A, Lacchini R, et al. Matrix metalloproteinase (MMP)-2 gene polymorphisms affect circulating MMP-2 levels in patients with migraine with aura. Gene 2013;512:35–40. 13 Martins-Oliveira A, Goncalves FM, Speciali JG, et al. Specific matrix metalloproteinase 9 (MMP-9) haplotype affect the circulating MMP-9 levels in women with migraine. J Neuroimmunol 2012;252:89–94. 14 Gerlach RF, Demacq C, Jung K, et al. Rapid separation of serum does not avoid artificially higher matrix metalloproteinase (MMP)-9 levels in serum versus plasma. Clin Biochem 2007;40:119–23.
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Targeting matrix metalloproteinases in disease conditions Michele M Castro, Jose E Tanus-Santos Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil Correspondence to Professor Jose E Tanus-Santos, Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP 14049-900, Brazil; [email protected]; [email protected] Accepted 18 August 2014 Published Online First 5 September 2014
▸ http://dx.doi.org/10.1136/ acupmed-2014-010612
To cite: Castro MM, TanusSantos JE. Acupunct Med 2014;32:373–375.
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that are specialised to degrade extracellular protein assemblies which provide cells with much of the structural and biochemical apparatus. The members of this structure-related family of proteases, comprising more than 25 members, differ from each other, particularly in their location in the cell and the specificity of substrate proteolysis. The gelatinases, referred to as MMP-2 and MMP-9, are the main contributors to many cardiovascular diseases.1 For example, by degrading extracellular proteins such as collagen and elastin, MMP-2 triggers proliferation and migration of many cell types, thus favouring conditions ranging from angiogenesis and embryogenesis to hypertension, aortic aneurysm, inflammation and cancer.2 To protect MMPs from abnormal autoproteolysis or uncontrolled tissue degradation, MMPs are synthesised with an autoinhibitory propeptide which binds its cysteine thiol to the zinc ion in the catalytic domain. As soon as MMPs are secreted from cells the cysteine–zinc bond is disrupted by other proteases or by oxidising compounds, setting free the catalytic domain.1 Tissue inhibitors of MMPs (TIMPs) are the main inhibitors of MMP activity and bind to the catalytic site of MMPs non-covalently in a 1:1 stoichiometric ratio. Among four TIMPs, TIMP-2 binds preferentially to MMP-2 while TIMP-1 binds to MMP-9.1 In fact, increased MMP-9 and MMP-2 activities have been implicated in many inflammatory and degenerative brain diseases such as Alzheimer’s disease, multiple sclerosis, stroke and migraine. They may degrade proteins of the basement membrane in the brain vasculature, thus impairing the blood–brain barrier and favouring the influx of inflammatory cells and cytokines (figure 1), disrupting myelin.3 Although migraine is a common neurovascular disorder, its precise pathophysiology is not fully understood. Many studies
Castro MM, et al. Acupunct Med 2014;32:373–375. doi:10.1136/acupmed-2014-010649
suggest increased cortical activity (cortical spreading depression) which may cause blood–brain barrier destabilisation, meningeal inflammation and abnormal activation of nociceptors in the trigeminal nucleus.4 As MMPs may disrupt the blood–brain barrier in many neurological diseases, they are increasingly considered as potential targets in migraine (figure 1). In this respect, an increased plasma MMP-9/TIMP-1 ratio was shown in patients with migraine without aura compared with healthy controls.5 Other groups have also shown increased MMP-9 levels in the plasma of patients with migraine without aura during and between attacks.6 7 Increased MMP-9 release from inflammatory cells apparently disrupts the blood–brain barrier and contributes to cortical spreading depression-induced meningeal inflammation and migraine.8 Furthermore, we described for the first time increased plasma levels of MMP-2 and MMP-2/ TIMP-2 ratios in patients with migraine with and without aura.5 As MMP-2 is one of the main proteases involved in cardiovascular maladaptive changes in many diseases,2 higher levels of MMP-2 in patients with migraine may be a risk factor for the development of cardiovascular diseases. However, it is uncertain which mechanisms could be activated by MMP-2 to promote migraine. It is possible that MMP-2 cleaves the basement membrane of the surrounding vasculature, thus contributing to blood–brain barrier disruption, increased vascular permeability and inflammation. In this issue, Cayir et al9 examined the effects of acupuncture therapy on the circulating levels of MMP-2 in patients with migraine with and without aura. Acupuncture may exert anti-inflammatory effects10 and alleviate pain by stimulating the analgesic effects of some endogenous opioids. While the circulating MMP-2 levels were not modified by acupuncture, serum MMP-2 activity decreased 373
Editorial
Figure 1 Increased activity of matrix metalloproteinase-9 (MMP-9) and MMP-2 during migraine may degrade the basement membrane in the surrounding vasculature, thus disrupting the blood–brain barrier (BBB). It favours the influx of inflammatory cells to the brain, thus contributing to cortical spreading depression-induced meningeal inflammation and migraine. The mechanisms exerted by acupuncture to reduce inflammatory cell infiltration and migraine are not yet known. It is possible that acupuncture suppresses oxidative stress and then contributes to decrease MMP-9 and MMP-2 activity in the brain. Copyright Castro and Tanus-Santos.
significantly after the first and last session of acupuncture (total of 10) compared with baseline conditions. They also observed an amelioration in general health perception ( physical and mental) among the patients with migraine. While the mechanisms behind acupuncture-induced decreases in MMP-2 activity are uncertain, the authors speculated that the antiinflammatory effects exerted by acupuncture may contribute to lessen MMP-2 activity. It is also possible that acupuncture therapy may have suppressed oxidative stress by increasing the activity of antioxidant enzymes, as previously shown.10 Supporting this suggestion, attenuation of oxidative stress decreased MMP-2 activity very significantly.11 While Cayir et al9 have not measured TIMP-2 levels in their study, it is possible that acupuncture therapy may have increased TIMP-2 levels, thus decreasing MMP-2 activity without significantly changing MMP-2 levels. In addition, the genetic contribution to the variability in the responses found by Cayir et al has not been examined, and it is well known that genetic variations may affect the susceptibility of patients to develop diseases. Interestingly, MMP-2 polymorphisms and haplotypes ( particular combinations of genetic markers) may also affect circulating levels of MMP-2 and MMP-2/TIMP-2 ratios in patients with migraine.12 Moreover, a specific MMP-9 haplotype was associated with increased plasma MMP-9 concentrations in migraine patients, thus 374
predisposing them to the disease.13 It is therefore possible that therapies designed to mitigate MMP activity may be more efficient in some patients, particularly those predisposed to increased MMP levels. These issues remain to be studied in the context of the responses to acupuncture. The study by Cayir et al focused on serum MMP-2 levels. Further studies examining circulating MMP levels should take into consideration the fact that serum measurements are not appropriate for all MMPs, particularly MMP-9, because MMP-9 levels are artificially higher in serum than in plasma.14 In addition to using the appropriate samples and a control (sham) group, further studies should also take into consideration concomitant diseases and medications used by patients with migraine. These factors may significantly affect MMP concentrations and should be controlled for. Competing interests None. Provenance and peer review Not commissioned; internally peer reviewed.
REFERENCES 1 Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003;92:827–39. 2 Castro MM, Tanus-Santos JE. Inhibition of matrix metalloproteinases (MMPs) as a potential strategy to ameliorate
Castro MM, et al. Acupunct Med 2014;32:373–375. doi:10.1136/acupmed-2014-010649
Editorial
3
4 5
6 7
8
9
hypertension-induced cardiovascular alterations. Curr Drug Targets 2013;14:335–43. Yong VW, Power C, Forsyth P, et al. Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci 2001;2:502–11. Silberstein SD. Migraine. Lancet 2004;363:381–91. Martins-Oliveira A, Speciali JG, Dach F, et al. Different circulating metalloproteinase profiles in women with migraine with and without aura. Clin Chim Acta 2009;408:60–4. Leira R, Sobrino T, Rodriguez-Yanez M, et al. MMP-9 immunoreactivity in acute migraine. Headache 2007;47:698–702. Imamura K, Takeshima T, Fusayasu E, et al. Increased plasma matrix metalloproteinase-9 levels in migraineurs. Headache 2008;48:135–9. Gursoy-Ozdemir Y, Qiu J, Matsuoka N, et al. Cortical spreading depression activates and upregulates MMP-9. J Clin Invest 2004;113:1447–55. Cayir Y, Ozdemir G, Celik M, et al. Acupuncture decreases matrix metalloproteinase-2 activity in migraine patients. Acupunct Med 2014;32:376–80.
Castro MM, et al. Acupunct Med 2014;32:373–375. doi:10.1136/acupmed-2014-010649
10 Leung MC, Yip KK, Ho YS, et al. Mechanisms underlying the effect of acupuncture on cognitive improvement: a systematic review of animal studies. J Neuroimmune Pharmacol 2014;9:492–507. 11 Castro MM, Rizzi E, Rodrigues GJ, et al. Antioxidant treatment reduces matrix metalloproteinase-2-induced vascular changes in renovascular hypertension. Free Radic Biol Med 2009;46:1298–307. 12 Goncalves FM, Martins-Oliveira A, Lacchini R, et al. Matrix metalloproteinase (MMP)-2 gene polymorphisms affect circulating MMP-2 levels in patients with migraine with aura. Gene 2013;512:35–40. 13 Martins-Oliveira A, Goncalves FM, Speciali JG, et al. Specific matrix metalloproteinase 9 (MMP-9) haplotype affect the circulating MMP-9 levels in women with migraine. J Neuroimmunol 2012;252:89–94. 14 Gerlach RF, Demacq C, Jung K, et al. Rapid separation of serum does not avoid artificially higher matrix metalloproteinase (MMP)-9 levels in serum versus plasma. Clin Biochem 2007;40:119–23.
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