Biology of Tissue Inhibitor of Metalloproteinase 3 (TIMP3), and Its Therapeutic Implications in Cardiovascular Pathology

Fan, Daiming; Kassiri, Zamaneh

doi:10.3389/fphys.2020.00661

Cited by 93 publications

(85 citation statements)

References 171 publications

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“…This correlation between Timp1 and Cd63 expression is also noted in chondroblasts (Table S9), a relationship that may function to mediate cell survival/proliferation under conditions where there is reduced Mmp expression described elsewhere [16]. In contradistinction to the restricted, inducible expression of Timp1, we find that Timp3 is highly expressed in many normal tissues, particularly within the vascular and renal systems [34,35] (Figures 5, S1 & S2). Vascular and tubular cells are exposed to fluid shear stress from the flow of fluid [36,37].…”

Section: Discussionsupporting

confidence: 71%

Whole Organism Profiling of the Timp Gene Family

Peeney

Fan²,

Gurung

et al. 2021

Preprint

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Tissue inhibitor of metalloproteinases (TIMPs/Timps) are an endogenous family of widely expressed matrisome-associated proteins that were initially identified as inhibitors of matrix metalloproteinase activity (Metzincin family proteases). Consequently, TIMPs are often considered simply as protease inhibitors by many investigators. However, an evolving list of new metalloproteinase-independent functions for TIMP family members suggests that this concept is outdated. These novel TIMP functions include direct agonism/antagonism of multiple transmembrane receptors, as well as interactions with matrisome targets. While the family was fully identified over 2 decades ago, there has yet to be an in-depth study describing the expression of TIMPs in normal tissues of adult mammals. An understanding of the tissues and cell-types that express TIMPs 1 through 4, in both normal and disease states are important to contextualize the growing functional capabilities of TIMP proteins, which are often dismissed as non-canonical. Using publicly available single cell RNA sequencing data from the Tabula Muris Consortium, we analyzed approximately 100,000 murine cells across nineteen tissues from non-diseased organs, representing seventy-three annotated cell types, to define the diversity in Timp gene expression across healthy tissues. We describe that Timp genes display unique expression profiles across tissues and organ-specific cell types. Within annotated cell-types, we identify clear and discrete cluster-specific patterns of Timp expression, particularly in cells of stromal and endothelial origins. Differential expression and gene set pathway analysis provide evidence of the biological significance of Timp expression in these identified cell sub-types, which are consistent with novel roles in normal tissue homeostasis and changing roles in disease progression. This understanding of the tissues, specific cell types and conditions of the microenvironment in which Timp genes are expressed adds important physiological context to the growing array of novel TIMP protein functions.

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Section: Discussionsupporting

confidence: 71%

Whole Organism Profiling of the Timp Gene Family

Peeney

Fan²,

Gurung

et al. 2021

Preprint

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“…In intact MSCs, the expression of TIMP1 and TIMP3 were downregulated after 10 days of SMG, which suggests the probable increased activity of MMPs. It is known that TIMP3 inhibits a wide range of matrix metalloproteinases such as MMP1, MMP2, MMP3, MMP7, MMP9, MMP13, MMP14, and MMP15 [ 65 ]. The effect of protease inhibitor reduction can be assumed to prevail due to the fact that each of them is capable of inhibiting more than one MMP.…”

Section: Discussionmentioning

confidence: 99%

Simulated Microgravity Remodels Extracellular Matrix of Osteocommitted Mesenchymal Stromal Cells

Zhivodernikov

Ratushnyy

Буравкова

2021

IJMS

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The extracellular matrix (ECM) is the principal structure of bone tissue. Long-term spaceflights lead to osteopenia, which may be a result of the changes in composition as well as remodeling of the ECM by osteogenic cells. To elucidate the cellular effects of microgravity, human mesenchymal stromal cells (MSCs) and their osteocommitted progeny were exposed to simulated microgravity (SMG) for 10 days using random positioning machine (RPM). After RPM exposure, an imbalance of MSC collagen/non-collagen ratio at the expense of a decreased level of collagenous proteins was detected. At the same time, the secretion of proteases (cathepsin A, cathepsin D, MMP3) was increased. No significant effects of SMG on the expression of stromal markers and cell adhesion molecules on the MSC surface were noted. Upregulation of COL11A1, CTNND1, TIMP3, and TNC and downregulation of HAS1, ITGA3, ITGB1, LAMA3, MMP1, and MMP11 were detected in RPM exposed MSCs. ECM-associated transcriptomic changes were more pronounced in osteocommitted progeny. Thus, 10 days of SMG provokes a decrease in the collagenous components of ECM, probably due to the decrease in collagen synthesis and activation of proteases. The presented data demonstrate that ECM-associated molecules of both native and osteocommitted MSCs may be involved in bone matrix reorganization during spaceflight.

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“…An excess amount of proteases will lead to increased anabolic or catabolic ECM proteolysis while increasing the amount of protease inhibitors, such as TIMPs, will decrease or stop ECM proteolysis and protect tissues from excessive ECM turnover. There are four TIMP isotypes, which can inhibit virtually all metalloproteinases including MMPs, the pericellular ADAM proteases and ADAMTS proteases, albeit with different specificities and efficiencies for the individual protease families ( Brew and Nagase, 2010 ; Arpino et al, 2015 ; Fan and Kassiri, 2020 ). For ADAMTS proteases, TIMP3 appears to be the most potent TIMP in vivo .…”

Section: Inhibitors Of Adamts Proteasesmentioning

confidence: 99%

Regulation of ADAMTS Proteases

Rose

Taye

Karoulias

et al. 2021

Front. Mol. Biosci.

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A disintegrin and metalloprotease with thrombospondin type I motifs (ADAMTS) proteases are secreted metalloproteinases that play key roles in the formation, homeostasis and remodeling of the extracellular matrix (ECM). The substrate spectrum of ADAMTS proteases can range from individual ECM proteins to entire families of ECM proteins, such as the hyalectans. ADAMTS-mediated substrate cleavage is required for the formation, remodeling and physiological adaptation of the ECM to the needs of individual tissues and organ systems. However, ADAMTS proteases can also be involved in the destruction of tissues, resulting in pathologies such as arthritis. Specifically, ADAMTS4 and ADAMTS5 contribute to irreparable cartilage erosion by degrading aggrecan, which is a major constituent of cartilage. Arthritic joint damage is a major contributor to musculoskeletal morbidity and the most frequent clinical indication for total joint arthroplasty. Due to the high sequence homology of ADAMTS proteases in their catalytically active site, it remains a formidable challenge to design ADAMTS isotype-specific inhibitors that selectively inhibit ADAMTS proteases responsible for tissue destruction without affecting the beneficial functions of other ADAMTS proteases. In vivo, proteolytic activity of ADAMTS proteases is regulated on the transcriptional and posttranslational level. Here, we review the current knowledge of mechanisms that regulate ADAMTS protease activity in tissues including factors that induce ADAMTS gene expression, consequences of posttranslational modifications such as furin processing, the role of endogenous inhibitors and pharmacological approaches to limit ADAMTS protease activity in tissues, which almost exclusively focus on inhibiting the aggrecanase activity of ADAMTS4 and ADAMTS5.

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Biology of Tissue Inhibitor of Metalloproteinase 3 (TIMP3), and Its Therapeutic Implications in Cardiovascular Pathology

Cited by 93 publications

References 171 publications

Whole Organism Profiling of the Timp Gene Family

Whole Organism Profiling of the Timp Gene Family

Simulated Microgravity Remodels Extracellular Matrix of Osteocommitted Mesenchymal Stromal Cells

Regulation of ADAMTS Proteases

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