Cathepsin K-deficiency impairs mouse cardiac function after myocardial infarction

Fang, Wenqian; He, Aina; Xiang, Meixiang; Lin, Yan; Wang, Yajun; Li, Jie; Yang, Chengzhang; Zhang, Xian; Liu, Cong-Lin; Sukhova, Galina K.; Barascuk, Natasha; Larsen, Lise; Karsdal, Morten A.; Libby, Peter; Shi, Guo‐Ping

doi:10.1016/j.yjmcc.2018.11.010

Cited by 19 publications

(16 citation statements)

References 55 publications

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“…However, not all functions of extracellular cysteine cathepsins in the cardiovascular system are harmful. A recent study has shown that cathepsin K has a pivotal role in cardiac remodeling following myocardial infarction, since sufficient collagen degradation is needed to reduce cardiac fibrosis [93]. However, processing of membrane-bound chemokine fractalkine (CX 3 CL1 or (C-X3-C motif) ligand 1) by cathepsin S homes additional inflammatory cells to the site of atherogenesis, thereby sustaining the inflammation and progressing the pathology [157].…”

Section: Ecm Proteolysis and The Cathepsinsmentioning

confidence: 99%

Cysteine Cathepsins and their Extracellular Roles: Shaping the Microenvironment

Vidak

Javoršek

Vizovišek

et al. 2019

Cells

271

228

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: For a long time, cysteine cathepsins were considered primarily as proteases crucial for nonspecific bulk proteolysis in the endolysosomal system. However, this view has dramatically changed, and cathepsins are now considered key players in many important physiological processes, including in diseases like cancer, rheumatoid arthritis, and various inflammatory diseases. Cathepsins are emerging as important players in the extracellular space, and the paradigm is shifting from the degrading enzymes to the enzymes that can also specifically modify extracellular proteins. In pathological conditions, the activity of cathepsins is often dysregulated, resulting in their overexpression and secretion into the extracellular space. This is typically observed in cancer and inflammation, and cathepsins are therefore considered valuable diagnostic and therapeutic targets. In particular, the investigation of limited proteolysis by cathepsins in the extracellular space is opening numerous possibilities for future break-through discoveries. In this review, we highlight the most important findings that establish cysteine cathepsins as important players in the extracellular space and discuss their roles that reach beyond processing and degradation of extracellular matrix (ECM) components. In addition, we discuss the recent developments in cathepsin research and the new possibilities that are opening in translational medicine.

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Section: Ecm Proteolysis and The Cathepsinsmentioning

confidence: 99%

Cysteine Cathepsins and their Extracellular Roles: Shaping the Microenvironment

Vidak

Javoršek

Vizovišek

et al. 2019

Cells

271

228

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“…Collectively, these serial studies hint the crucial role of CatK in cardiac dysfunction. Intriguingly, a recent study by Fang et al (2019) showed that the plasma CatK levels were significantly increased in patients with coronary heart diseases (CHD) particularly in those with acute myocardial infarction (MI) when compared to non-CHD controls. They further detected the elevated CatK expression in heart from the post-MI mouse, which mainly localized to cardiomyocytes, ECs, fibroblasts, macrophages and CD4 +++ T cells as well.…”

Section: Cardiovascular Systemmentioning

confidence: 99%

Cathepsin K: The Action in and Beyond Bone

Dai

Chu

et al. 2020

Front. Cell Dev. Biol.

118

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Cathepsin K (CatK) is one of the most potent proteases in lysosomal cysteine proteases family, of which main function is to mediate bone resorption. Currently, CatK is among the most attractive targets for anti-osteoporosis drug development. Although many pharmaceutical companies are working on the development of selective inhibitors for CatK, there is no FDA approved drug till now. Odanacatib (ODN) developed by Merck & Co. is the only CatK inhibitor candidate which demonstrated high therapeutic efficacy in patients with postmenopausal osteoporosis in Phase III clinical trials. Unfortunately, the development of ODN was finally terminated due to the cardio-cerebrovascular adverse effects. Therefore, it arouses concerns on the undesirable CatK inhibition in non-bone sites. It is known that CatK has far-reaching actions throughout various organs besides bone. Many studies have also demonstrated the involvement of CatK in various diseases beyond the musculoskeletal system. This review not only summarized the functional roles of CatK in bone and beyond bone, but also discussed the potential relevance of the CatK action beyond bone to the adverse effects of inhibiting CatK in non-bone sites.

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“…Our attempt to identify the protease for this isoform focused on cathepsin K, a cysteine protease previously studied in osteoblasts with recently recognized roles in the cardiovascular system. 37,38 The top three in silico predicted cleavage sites were conserved between human and mouse: 138 aa, 776 aa, and 919 aa. 39 The latter two sites could generate C-terminal cleaved proteins with predicted sizes of 80 kDa and 96 kDa, matching the $90 kDa observed.…”

Section: Discussionmentioning

confidence: 99%

Loss of full-length pumilio 1 abrogates miRNA-221-induced gene p27 silencing-mediated cell proliferation in the heart

Zhou¹,

Ng²,

Richards³

et al. 2022

Molecular Therapy - Nucleic Acids

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Upregulated expression of microRNA (miR)-221 is associated with downregulation of p27 and subsequent increased cell proliferation in a variety of human cancers. It is unknown whether miR-221 mimics could trigger neoplastic cellular proliferation.In vitro, we demonstrated miR-221 significantly downregulates the expression of P27 and increases proliferation of H9c2 and cardiac fibroblasts. The knockdown of PUM1 but not PUM2 abolished such effects by miR-221, as verified by RT-qPCR and western blot, direct binding of p27 3 0 UTR by luciferase reporter assay and cell proliferation by Ki67. In vivo expression of P27 in the rat liver, heart, kidney, spleen, and muscle were not affected by miR-221 at 1 and 4 mg/kg and concurrently fulllength (FL) PUM1 (140 kDa) was not detected. Instead, isoforms of 105 and 90 kDa were observed and generated through alternative RNA slicing verified by cDNA cloning and sequencing and cathepsin K cleavage confirmed by studies with the inhibitor odanacatib. This is the first study to address the possible pro-proliferative effects of miR-221 mimic therapeutics in cardiovascular applications. Loss of FL PUM1 expression is a key factor abrogating miR-221-mediated p27 regulation, although other concurrent mechanisms cannot be excluded. Our findings provide essential insights into the context-dependent nature of miRNA functionality.

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Cathepsin K-deficiency impairs mouse cardiac function after myocardial infarction

Cited by 19 publications

References 55 publications

Cysteine Cathepsins and their Extracellular Roles: Shaping the Microenvironment

Cysteine Cathepsins and their Extracellular Roles: Shaping the Microenvironment

Cathepsin K: The Action in and Beyond Bone

Loss of full-length pumilio 1 abrogates miRNA-221-induced gene p27 silencing-mediated cell proliferation in the heart

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