TIMP-1 resistant matrix metalloproteinase-9 is the predominant serum active isoform associated with MRI activity in patients with multiple sclerosis

Trentini, Alessandro; Manfrinato, Maria Cristina; Castellazzi, Massimiliano; Tamborino, Carmine; Roversi, Gloria; Volta, Carlo Alberto; Baldi, Eleonora; Tola, Maria Rosaria; Granieri, Enrico; Dallocchio, Franco; Bellini, Tiziana; Fainardi, Enrico; Casetta, Ilaria; Mr, Tola; Rizzo, Roberta; Rotola, Antonella; Luca, Dario Di; Seraceni, Silva; Contini, Carlo; Sabbioni, Silvia; Negrini, Massimo; Tognon, M. L.; Antonelli, Tiziana; Groppo, Elisabetta; Gentile, Mauro; Caniatti, M. L.; Ceruti, Stefano; Manfrinato, MR; Bortolotti, Daria; Miotto, Eliane Correa; Ferracin, Manuela; Mazzoni, Elisa; Pietrobon, Silvia; Masini, Irene; Rotondo, John Charles; Martini, Fernanda; Baruzzi, Antônio Cláudio do Amaral; D’Alessandro, R; Michelucci, Roberto; Salvi, Fabrizio; Stecchi, S.; Scandellari, C.; Terzano, Giovanni; Granella, Franco; Nichelli, Paolo Frigio; Sola, Patrizia; Ferraro, Diana; Vitetta, Francesca; Simone, Am; Bedin, Roberta; Marcello, Norina; Motti, L.; Montepietra, Sara; Guidetti, Donata; Immovilli, Paolo; Montanari, E.; Pesci, Ilaria; Guareschi, A; Greco, Graciela; Santangelo, Mario; Am, Mauro; Malagù, Susanna; Rasi, F; Spadoni, M. A.; Galeotti, M.; Fiorani, L; Neri, Walter; Ravasio, Alessandro; Pasquinelli, M; Gutman, S.; Monaldini, C.

doi:10.1177/1352458514560925

Cited by 23 publications

(18 citation statements)

References 33 publications

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“…In light of the above considerations, we set out the present study with the aim to evaluate the contribution of MMPs, namely, active MMP-9 and MMP-2, and the cytokines/chemokines IL-17, IL-18, IL-23, and MCP-3 to the pathogenesis of MS. More importantly, for the first time we evaluated the possible intercorrelations involving these two classes of molecules. In agreement with previous studies [ 31 , 38 ], we found that serum active MMP-9 was higher in patients with MS and OND compared to healthy controls, whereas the CSF active MMP-9 was selectively elevated in MS patients. On the contrary, our finding of the lack of association between serum and CSF levels of active MMP-2 and MS disagrees with previous observations [ 32 ].…”

Section: Discussionsupporting

confidence: 93%

Interplay between Matrix Metalloproteinase-9, Matrix Metalloproteinase-2, and Interleukins in Multiple Sclerosis Patients

et al. 2016

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Matrix Metalloproteases (MMPs) and cytokines have been involved in the pathogenesis of multiple sclerosis (MS). However, no studies have still explored the possible associations between the two families of molecules. The present study aimed to evaluate the contribution of active MMP-9, active MMP-2, interleukin- (IL-) 17, IL-18, IL-23, and monocyte chemotactic proteins-3 to the pathogenesis of MS and the possible interconnections between MMPs and cytokines. The proteins were determined in the serum and cerebrospinal fluid (CSF) of 89 MS patients and 92 other neurological disorders (OND) controls. Serum active MMP-9 was increased in MS patients and OND controls compared to healthy subjects (p < 0.001 and p < 0.01, resp.), whereas active MMP-2 and ILs did not change. CSF MMP-9, but not MMP-2 or ILs, was selectively elevated in MS compared to OND (p < 0.01). Regarding the MMPs and cytokines intercorrelations, we found a significant association between CSF active MMP-2 and IL-18 (r = 0.3, p < 0.05), while MMP-9 did not show any associations with the cytokines examined. Collectively, our results suggest that active MMP-9, but not ILs, might be a surrogate marker for MS. In addition, interleukins and MMPs might synergistically cooperate in MS, indicating them as potential partners in the disease process.

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Section: Discussionsupporting

confidence: 93%

Interplay between Matrix Metalloproteinase-9, Matrix Metalloproteinase-2, and Interleukins in Multiple Sclerosis Patients

et al. 2016

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“…C). MMP‐9, a matrix metalloproteinase associated with the opened blood brain barrier in MS, and its inhibitor, TIMP‐1, were chosen due to their validated relationship to the MS disease process . TIMP‐1 showed no statistical difference between HV and MS monocytes, but was significantly increased upon both myelin phagocytosis and pioglitazone treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

Pioglitazone regulates myelin phagocytosis and multiple sclerosis monocytes

Natrajan

Komori

Kósa

et al. 2015

Ann Clin Transl Neurol

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ObjectiveMultiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Myeloid phagocytes, including blood monocytes recruited to demyelinating lesions, may play a dual role in MS: on one hand, they might enhance CNS damage after differentiating toward a proinflammatory phenotype; on the other, they promote remyelination and repair through effective phagocytosis of myelin debris. We have previously determined that the retinoid X receptor (RXR) plays an important role in monocyte phagocytosis of myelin. Peroxisome proliferator‐activated receptor γ is an RXR binding partner that plays a key role in myeloid cell biology and is targeted by the thiazolidinedione group of antidiabetics such as pioglitazone. Consequently, the purpose of this study was to determine if monocyte functions and differentiation profiles differ in MS patients compared to healthy volunteers (HV) and whether pioglitazone can reverse these differences to promote CNS recovery.MethodsMonocytes were isolated from MS patients and HV (n ≥ 36/group), and their ability to phagocytose myelin and modulate inflammation in the presence/absence of 1 μmol/L pioglitazone (the in vivo achievable concentration) was quantified by flow cytometry, transcriptional profiling, and proteomic assays.Results MS monocytes display impaired phagocytosis of myelin debris and enhanced proinflammatory differentiation. Pioglitazone treatment causes partial normalization of identified monocyte abnormalities in MS and fully reverses the deficit in myelin phagocytosis.InterpretationThese findings suggest that by inhibiting proinflammatory differentiation of monocytes and enhancing their phagocytosis of myelin, pioglitazone may be a useful adjunct therapy to immunomodulatory agents that target dysregulated adaptive immunity in MS.

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“…Indeed, immune cells mediate both neuro-inflammation and partly axonal damage, the two main disease hallmarks leading to disease progression and increased patients' disability. Basically, MS patients exhibit an impaired Blood Brain Barrier (BBB), which indicates infiltration of leukocyte into the CNS, reflecting in increased circulating levels of active Matrix Metalloproteinases (MMPs) [109][110][111]. The same is true for pro-inflammatory cytokines, which are found to be deranged and increased both in blood and cerebrospinal fluid (CSF) of MS patients compared to controls [112,113].…”

Section: Sex Disparity In Multiple Sclerosismentioning

confidence: 99%

“…Despite the evident importance of the aforementioned biomarkers in MS physiopathology, the possible dualistic influence of sex on the MS features in relation to their levels is still largely unexplored. This is particularly evident for MMPs, for which the paucity of in vivo studies have only examined cohorts of patients without MS, despite the undisputed importance of these enzymes in the disease [110]. The few studies on MS reported an upregulation of MMP-9 in peripheral blood mononuclear cells (PBMCs) of females with the RR form [117] and a decreased expression of MMP-9 following treatment with estriol in the preclinical model of the disease [118].…”

Section: Sex Disparity In Multiple Sclerosismentioning

confidence: 99%

“Bridging the Gap” Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era

Gemmati

Varani

Bramanti

et al. 2019

IJMS

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Gender medicine is the first step of personalized medicine and patient-centred care, an essential development to achieve the standard goal of a holistic approach to patients and diseases. By addressing the interrelation and integration of biological markers (i.e., sex) with indicators of psychological/cultural behaviour (i.e., gender), gender medicine represents the crucial assumption for achieving the personalized health-care required in the third millennium. However, ‘sex’ and ‘gender’ are often misused as synonyms, leading to frequent misunderstandings in those who are not deeply involved in the field. Overall, we have to face the evidence that biological, genetic, epigenetic, psycho-social, cultural, and environmental factors mutually interact in defining sex/gender differences, and at the same time in establishing potential unwanted sex/gender disparities. Prioritizing the role of sex/gender in physiological and pathological processes is crucial in terms of efficient prevention, clinical signs’ identification, prognosis definition, and therapy optimization. In this regard, the omics-approach has become a powerful tool to identify sex/gender-specific disease markers, with potential benefits also in terms of socio-psychological wellbeing for each individual, and cost-effectiveness for National Healthcare systems. “Being a male or being a female” is indeed important from a health point of view and it is no longer possible to avoid “sex and gender lens” when approaching patients. Accordingly, personalized healthcare must be based on evidence from targeted research studies aimed at understanding how sex and gender influence health across the entire life span. The rapid development of genetic tools in the molecular medicine approaches and their impact in healthcare is an example of highly specialized applications that have moved from specialists to primary care providers (e.g., pharmacogenetic and pharmacogenomic applications in routine medical practice). Gender medicine needs to follow the same path and become an established medical approach. To face the genetic, molecular and pharmacological bases of the existing sex/gender gap by means of omics approaches will pave the way to the discovery and identification of novel drug-targets/therapeutic protocols, personalized laboratory tests and diagnostic procedures (sex/gender-omics). In this scenario, the aim of the present review is not to simply resume the state-of-the-art in the field, rather an opportunity to gain insights into gender medicine, spanning from molecular up to social and psychological stances. The description and critical discussion of some key selected multidisciplinary topics considered as paradigmatic of sex/gender differences and sex/gender inequalities will allow to draft and design strategies useful to fill the existing gap and move forward.

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TIMP-1 resistant matrix metalloproteinase-9 is the predominant serum active isoform associated with MRI activity in patients with multiple sclerosis

Abstract: Our findings suggested that the TIMP-1 resistant MMP-9 seem to be the predominantly active isoform contributing to MS disease activity.

Cited by 23 publications

References 33 publications

Interplay between Matrix Metalloproteinase-9, Matrix Metalloproteinase-2, and Interleukins in Multiple Sclerosis Patients

Interplay between Matrix Metalloproteinase-9, Matrix Metalloproteinase-2, and Interleukins in Multiple Sclerosis Patients

Pioglitazone regulates myelin phagocytosis and multiple sclerosis monocytes

“Bridging the Gap” Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era

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