Whole organism profiling of the Timp gene family

Peeney, David; Fan, Yu; Gurung, Sadeechya; Lazaroff, Carolyn; Ratnayake, Shashikala; Warner, Andrew; Karim, Baktiar O.; Meerzaman, Daoud; Stetler‐Stevenson, William G.

doi:10.1016/j.mbplus.2023.100132

Cited by 5 publications

(2 citation statements)

References 48 publications

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“…Four TIMPs exist, sharing 40% sequence homology with each other [ 25 ]. In contrast to TIMP1, TIMP2, and TIMP3, which are ubiquitously expressed, TIMP4 is predominantly expressed in the brain and heart [ 21 , 23 , 25 ]. Evidence suggests that TIMP4 is highly associated with cardiovascular functioning and disease, and that TIMP4 plays a role in inflammatory processes of human cardiovascular pathology [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Altered brain expression and cerebrospinal fluid levels of TIMP4 in cerebral amyloid angiopathy

Jäkel,

De Kort,

Stellingwerf

et al. 2024

acta neuropathol commun

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Cerebral amyloid angiopathy (CAA) is a highly prevalent and progressive pathology, involving amyloid-β (Aβ) deposition in the cerebral blood vessel walls. CAA is associated with an increased risk for intracerebral hemorrhages (ICH). Insight into the molecular mechanisms associated with CAA pathology is urgently needed, to develop additional diagnostic tools to allow for reliable and early diagnosis of CAA and to obtain novel leads for the development of targeted therapies. Tissue inhibitor of matrix metalloproteinases 4 (TIMP4) is associated with cardiovascular functioning and disease and has been linked to vascular dementia. Using immunohistochemistry, we studied occipital brain tissue samples of 57 patients with CAA (39 without ICH and 18 with ICH) and 42 controls, and semi-quantitatively assessed expression levels of TIMP4. Patients with CAA had increased vascular expression of TIMP4 compared to controls (p < 0.001), and in these patients, TIMP4 expression correlated with CAA severity (τb = 0.38; p = 0.001). Moreover, TIMP4 expression was higher in CAA-ICH compared to CAA-non-ICH cases (p = 0.024). In a prospective cross-sectional study of 38 patients with CAA and 37 age- and sex-matched controls, we measured TIMP4 levels in cerebrospinal fluid (CSF) and serum using ELISA. Mean CSF levels of TIMP4 were decreased in patients with CAA compared to controls (3.36 ± 0.20 vs. 3.96 ± 0.22 ng/ml, p = 0.033), whereas median serum levels were increased in patients with CAA (4.51 ng/ml [IQR 3.75–5.29] vs 3.60 ng/ml [IQR 3.11–4.85], p-9.013). Moreover, mean CSF TIMP4 levels were lower in CAA patients who had experienced a symptomatic hemorrhage compared to CAA patients who did not (2.13 ± 0.24 vs. 3.57 ± 0.24 ng/ml, p = 0.007). CSF TIMP4 levels were associated with CSF levels of Aβ40 (spearman r (rs) = 0.321, p = 0.009). In summary, we show that TIMP4 is highly associated with CAA and CAA-related ICH, which is reflected by higher levels in the cerebral vasculature and lower levels in CSF. With these findings we provide novel insights into the pathophysiology of CAA, and more specifically in CAA-associated ICH.

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Section: Introductionmentioning

confidence: 99%

Altered brain expression and cerebrospinal fluid levels of TIMP4 in cerebral amyloid angiopathy

Jäkel,

De Kort,

Stellingwerf

et al. 2024

acta neuropathol commun

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“…Developing strategies include the normalization of the microenvironment to support anti-tumor immune cell functions, reduce extracellular matrix turnover, and restore homeostatic mechanisms that prevent tumor progression (11,12). Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of metalloproteinase (MP) activity, with TIMP2 displaying the broadest expression profile of the family (13,14). In addition to their functions as inhibitors of MP activity, TIMPs demonstrate a growing list of MPindependent functions that include the regulation of growth factor signaling, cytokine-like signaling capabilities, and direct modulation of cell behavior (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Timp2 loss-of-function mutation and TIMP2 treatment in murine model of NSCLC: modulation of immunosuppression and oncogenic signaling

Peeney,

Kumar,

Singh

et al. 2023

Preprint

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Mounting evidence suggests that the tissue inhibitor of metalloproteinases-2 (TIMP2) can reduce tumor burden and metastasis. However, the demonstration of such anti-tumor activity and associated mechanisms using in vivo tumor models is lacking. The effects of a Timp2 functional mutation and administration of recombinant TIMP2 were examined in both orthotopic and heterotopic murine models of lung cancer using C57Bl/6 syngeneic Lewis Lung 2-luciferase 2 cells (LL2-luc2) cells. Mice harboring a functional mutation of TIMP2 (mT2) display markedly increased primary lung tumor growth, increased mortality, enriched vasculature, and enhanced infiltration of pro-tumorigenic, immunosuppressive myeloid cells. Treatment with recombinant TIMP2 reduced primary tumor growth in both mutant and wild-type (wt) mice. Comparison of transcriptional profiles of lung tissues from tumor-free, wt versus mT2 mice reveals only minor changes. However, lung tumor-bearing mice of both genotypes demonstrate significant genotype-dependent changes in gene expression following treatment with TIMP. In tumor-bearing wt mice, TIMP2 treatment reduced the expression of upstream oncogenic mediators, whereas treatment of mT2 mice resulted in an immunomodulatory phenotype. A heterotopic subcutaneous model generating metastatic pulmonary tumors demonstrated that daily administration of recombinant TIMP2 significantly downregulates the expression of heat shock proteins, suggesting a reduction of cell-stress responses. In summary, we describe how TIMP2 exerts novel, anti-tumor effects in a murine model of lung cancer and that rTIMP2 treatment supports a normalizing effect on the tumor microenvironment. Our findings show that TIMP2 treatment demonstrates significant potential as an adjuvant in the treatment of NSCLC.

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Tissue inhibitors of metalloproteinases are proteolytic targets of matrix metalloproteinase 9

Coates-Park,

Lazaroff,

Gurung

et al. 2023

Matrix Biology

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Whole organism profiling of the Timp gene family

Cited by 5 publications

References 48 publications

Altered brain expression and cerebrospinal fluid levels of TIMP4 in cerebral amyloid angiopathy

Altered brain expression and cerebrospinal fluid levels of TIMP4 in cerebral amyloid angiopathy

Timp2 loss-of-function mutation and TIMP2 treatment in murine model of NSCLC: modulation of immunosuppression and oncogenic signaling

Tissue inhibitors of metalloproteinases are proteolytic targets of matrix metalloproteinase 9

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