MMP-28 (15q21.1) Epilysiini

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810947/

Epilysin (MMP-28) was first cloned from the human keratinocyte and testis cDNA libraries, and is expressed in many tissues such as lung, placenta, heart, gastrointestinal tract and testis (Lohi et al., 2001). The enzyme expressed in basal keratinocytes in skin is considered to function in wound repair (Saarialho-Kere et al., 2002). It is also elevated in cartilage from patients with osteoarthritis and rheumatoid arthritis (Kevorkian et al., 2004; Momohara et al., 2004). Overexpression of recombinant MMP-28 in lung adenocarcinoma cells induces irreversible epithelial mesenchymal transition, accompanied by cell surface loss of E-cadherin, processing of latent TGFβ complex and increased levels of TGFβ, along with up-regulation of MT1-MMP and MMP-9 and collagen invasive activity (Illman et al., 2006).

Thesis 2018: TIMP3 (SFD) , MMP-28 (epilysiini) . Raamissa COPD ja IPF

J Proteomics. 2018 Oct 30;189:23-33. doi: 10.1016/j.jprot.2018.02.027. Epub 2018 Mar 1.

Quantitative proteomic characterization of the lung extracellular matrix in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.

Åhrman E¹, Hallgren O², Malmström L³, Hedström U⁴, Malmström A⁵, Bjermer L², Zhou XH⁶, Westergren-Thorsson G⁷, Malmström J⁸.

Abstract

Remodeling of the extracellular matrix (ECM) is a common feature in lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Here, we applied a sequential tissue extraction strategy to describe disease-specific remodeling of human lung tissue in disease, using end-stages of COPD and IPF. Our strategy was based on quantitative comparison of the disease proteomes, with specific focus on the matrisome, using data-independent acquisition and targeted data analysis (SWATH-MS). Our work provides an in-depth proteomic characterization of human lung tissue during impaired tissue remodeling. In addition, we show important quantitative and qualitative effects of the solubility of matrisome proteins. COPD was characterized by a disease-specific increase in ECM regulators, metalloproteinase inhibitor 3 (TIMP3) and matrix metalloproteinase 28 (MMP-28), whereas for IPF, impairment in cell adhesion proteins, such as collagen VI and laminins, was most prominent. For both diseases, we identified increased levels of proteins involved in the regulation of endopeptidase activity, with several proteins belonging to the serpin family. The established human lung quantitative proteome inventory and the construction of a tissue-specific protein assay library provides a resource for future quantitative proteomic analyses of human lung tissues. SIGNIFICANCE: We present a sequential tissue extraction strategy to determine changes in extractability of matrisome proteins in end-stage COPD and IPF compared to healthy control tissue. Extensive quantitative analysis of the proteome changes of the disease states revealed altered solubility of matrisome proteins involved in ECM regulators and cell-ECM communication. The results highlight disease-specific remodeling mechanisms associated with COPD and IPF.

KEYWORDS:

COPD; IPF; Lung tissue; Matrisome; Quantitative proteomics; SWATH-MS

PMID:

29501846

DOI:

10.1016/j.jprot.2018.02.027

TIMP3 ja sirtuiinit Laaja artikkeli josa piilee myös TIMP3

https://www.sciencedirect.com/science/article/pii/S0925443915000654

TIMP1/MMP tasapaino ja SIRTUIINI1: Raameissa COPD ja emfyseema

Abstract

Sirtuin1 (SIRT1), a protein/histone deacetylase, protects against the development of pulmonary emphysema. 

However, the molecular mechanisms underlying this observation remain elusive. The imbalance of tissue inhibitor of matrix metalloproteinases (TIMPs)/matrix metalloproteinases (MMPs) plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema.

 We hypothesized that SIRT1 protects against emphysema by redressing the imbalance between MMPs and TIMPs. 

To test this hypothesis, SIRT1 deficient and overexpressing/transgenic mice were exposed to cigarette smoke (CS). The protein level and activity of MMP-9 were increased in lungs of SIRT1 deficient mice exposed to CS as compared to WT littermates, which were attenuated by SIRT1 overexpression. SIRT1 deficiency decreased the level of TIMP-1, which was augmented in SIRT1 transgenic mice as compared to WT littermates by CS. However, the level of MMP-2, MMP-12, TIMP-2, TIMP-3, or TIMP-4 was not altered by SIRT1 in response to CS exposure. SIRT1 reduction was associated with imbalance of TIMP-1 and MMP-9 in lungs of smokers and COPD patients. 

Mass spectrometry and immunoprecipitation analyses revealed that TIMP-1 acetylation on specific lysine residues was increased, whereas its interaction with SIRT1 and MMP-9 was reduced in mouse lungs with emphysema, as well as in lungs of smokers and COPD patients. SIRT1 deficiency increased CS-induced TIMP-1 acetylation, and these effects were attenuated by SIRT1 overexpression. These results suggest that SIRT1 protects against COPD/emphysema via redressing the TIMP-1/MMP-9 imbalance involving TIMP-1 deacetylation. Thus, redressing the TIMP-1/MMP-9 imbalance by pharmacological activation of SIRT1 is an attractive approach in the intervention of COPD.

Kertauksena kaikki neljä TIMP ja niiden geenit

Kuvitella, niitä ei ole vieläkään enemmän kuin neljä kuten monta vuotta sitten. Tai sitten niitä ei ole kovin tarkkaan tutkittu. Ne ovat olleet aika huomaamattomia verrattuna MMP-joukon massiivisiin haitta-aikaansaannoksiin.

Niillä voi olla jokin muu oma funktio kuin vain olla MMPi.

 https://www.genenames.org/cgi-bin/genefamilies/set/892

Tissue inhibitor of metalloproteinase: The matrix metalloproteinases are inhibited by specific endogenous tissue inhibitors of metalloproteinases (TIMPs), which comprise a family of four protease inhibitors: TIMP1, TIMP2, TIMP3 and TIMP4. Overall, all MMPs are inhibited by TIMPs once they are activated but the gelatinases (MMP-2 and MMP- ) can form complexes with TIMPs when the enzymes are in the latent form. The complex of latent MMP-2 (pro-MMP-2)with TIMP-2 serves to facilitate the activation of pro-MMP-2 at the cell surface by MT1-MMP ( MMP-14 ), a membrane-anchored MMP. The role of the pro-MMP-9/TIMP-1 complex is still unknown. [Source: Wikipedia] 

Genes contained within the family: 4

l		TIMP1	TIMP1 metallopeptidase inhibitor 1 EPO, (Xp11.3)	TIMP2	TIMP 2metallopeptidase inhibitor 2 CSC-21K (17q25.3)	TIMP3	TIMP3 metallopeptidase inhibitor 3 SFD (22q12.3)	TIMP4	TIMP4 metallopeptidase inhibitor 4

TIMP-1

Function

Metalloproteinase inhibitor that functions by forming one to one complexes with target metalloproteinases, such as collagenases, and irreversibly inactivates them by binding to their catalytic zinc cofactor. Acts on MMP1, MMP2, MMP3, MMP7, MMP8, P9, MMP10, MMP11, MMP12, MMP13 and MMP16. Does not act on MMP14. Also functions as a growth factor that regulates cell differentiation, migration and cell death and activates cellular signaling cascades via CD63 and ITGB1. Plays a role in integrin signaling. Mediates erythropoiesis in vitro; but, unlike IL3, it is species-specific, stimulating the growth and differentiation of only human and murine erythroid progenitors.12 Publications

TIMP-2 

 

TIMP-3 

A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2.

Qi JH et al. Nat. Med. 2003 Apr;9(4):407-415

PMID: 12652295 Europe PMC Pubmed 

TACE, SIRT-1 ,TIMP-3, IBD, resveratroli

https://www.ncbi.nlm.nih.gov/pubmed/24548422

Cytokine. 2014 Mar;66(1):30-9. doi: 10.1016/j.cyto.2013.12.010. Epub 2014 Jan 4.

Involvement of TACE in colon inflammation: a novel mechanism of regulation via SIRT-1 activation.

Sharma M¹, Mohapatra J¹, Wagh A¹, Patel HM¹, Pandey D¹, Kadam S¹, Argade A², Deshpande SS³, Shah GB³, Chatterjee A⁴, Jain MR¹.

Abstract

TNF-α converting enzyme (TACE) processes the membrane TNF-α to release the bioactive soluble TNF-α. Several evidences suggest the involvement of TNF-α and TACE in inflammatory bowel disease (IBD). Tissue inhibitor of metalloproteinase (TIMP)-3, an endogenous inhibitor of TACE, is positively associated with silent information regulator (SIRT)-1. We aimed to study the expression of TACE, TIMP-3 and SIRT-1 at different stages of colitis and how TACE is regulated in response to SIRT-1 activation.

 Acute colitis was induced by 3.5% dextran sulfate sodium (DSS) in drinking water for 5days and levels of cytokines and mRNA expression of TACE, TIMP-3 and SIRT-1 were measured in colon at different time intervals. Next, the effect of SIRT-1 activator (resveratrol) or a selective TACE inhibitor (compound 11p) treatment was evaluated. Elevated levels of TNF-α, interleukin (IL)-6, IL-1β, interferon (IFN)-γ and IL-17 were observed during DSS exposure phase which restored to the normal level after DSS removal. A significant increase in TACE and suppression in TIMP-3 and SIRT-1 mRNA level was observed during DSS exposure phase which reverts back to normal towards the remission phase. Treatment with resveratrol significantly elevated SIRT-1 and TIMP-3 and suppressed TACE mRNA expression and was associated with amelioration of disease. Furthermore, treatment with selective TACE inhibitor significantly suppressed body weight loss, disease activity index, colonic myeloperoxidase activity and the elevated levels of cytokines after DSS challenge. These results strongly emphasize the involvement of TACE in colon inflammation and inhibition of TACE directly or indirectly via SIRT-1 activation ameliorates colitis.

KEYWORDS:

Inflammatory bowel disease; SIRT-1; TNF-α; TNF-α converting enzyme

PMID:

24548422

DOI:

10.1016/j.cyto.2013.12.010

ADAM17 ja EBOVgp