Cathepsin K

Brὂmme, Dieter

doi:10.1016/b978-0-12-382219-2.00409-9

Cited by 6 publications

(4 citation statements)

References 76 publications

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“…To build on the observed differences in Ctsk expression, we next sought to directly assess activity of cathepsin K protein. Importantly, cathepsin K can promote collagen resorption (33) but this collagenolytic activity can also be post-translationally modified (34, 35), requiring direct measurement of activity. To measure intracellular cathepsin K activity, we used a cell-permeable cathepsin k probe (MagicRed) which localizes to the lysosomes and fluoresces when cleaved by cathepsin K. We exposed freshly isolated cells to MagicRed and used flow cytometry to analyze cathepsin K activity in NAD(P)H high and NAD(P)H low populations.…”

Section: Resultsmentioning

confidence: 99%

A redox-shifted fibroblast subpopulation emerges in the fibrotic lung

Link,

Meridew,

Caporarello

et al. 2023

Preprint

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Idiopathic pulmonary fibrosis (IPF) is an aggressive and thus far incurable disease, characterized by aberrant fibroblast-mediated extracellular matrix deposition. Our understanding of the disease etiology is incomplete; however, there is consensus that a reduction-oxidation (redox) imbalance plays a role. In this study we use the autofluorescent properties of two redox molecules, NAD(P)H and FAD, to quantify changes in their relative abundance in living lung tissue of mice with experimental lung fibrosis, and in freshly isolated cells from mouse lungs and humans with IPF. Our results identify cell population-specific intracellular redox changes in the lungs in experimental and human fibrosis. We focus particularly on redox changes within collagen producing cells, where we identified a bimodal distribution of NAD(P)H concentrations, establishing NAD(P)Hhigh and NAD(P)Hlow sub-populations. NAD(P)Hhigh fibroblasts exhibited elevated pro-fibrotic gene expression and decreased collagenolytic protease activity relative to NAD(P)Hlow fibroblasts. The NAD(P)Hhigh population was present in healthy lungs but expanded with time after bleomycin injury suggesting a potential role in fibrosis progression. We identified a similar increased abundance of NAD(P)Hhigh cells in freshly dissociated lungs of subjects with IPF relative to controls, and similar reductions in collagenolytic activity in this cell population. These data highlight the complexity of redox state changes in experimental and human pulmonary fibrosis and the need for selective approaches to restore redox imbalances in the fibrotic lung.

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Section: Resultsmentioning

confidence: 99%

A redox-shifted fibroblast subpopulation emerges in the fibrotic lung

Link,

Meridew,

Caporarello

et al. 2023

Preprint

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“…We posit that strong electrostatic interactions of these clusters with negatively charged groups in the OFS-2 dyes interfere with the optimal alignment of the bound ligand for peptide bond cleavage. Taking into account that all the OFS probes have two to three negative charges at pH 5.5, the optimal pH for Ctsk, the relative OFS activation rates correlate with the number of sulfonate groups: four in OFS-2 (very slow peptide linker cleavage), two in OFS-3 (moderately efficient peptide linker cleavage), and none in OFS-1 (efficient peptide linker cleavage).…”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Cathepsin-K-Activated Osteoadsorptive Fluorogenic Sentinel (OFS) Probes for Detecting Early Osteoclastic Bone Resorption in a Multiple Myeloma Mouse Model

Richard

Morinaga²,

Zheng

et al. 2021

Bioconjugate Chem.

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We describe the design and synthesis of OFS-1, an Osteoadsorptive Fluorogenic Sentinel imaging probe that is adsorbed by hydroxyapatite (HAp) and bone mineral surfaces, where it generates an external fluorescent signal in response to osteoclastsecreted cathepsin K (Ctsk). The probe consists of a bone-anchoring bisphosphonate moiety connected to a Forster resonance energy transfer (FRET) internally quenched fluorescent (IQF) dye pair, linked by a Ctsk peptide substrate, GHPGGPQG. Key structural features contributing to the effectiveness of OFS-1 were defined by structure−activity relationship (SAR) and modeling studies comparing OFS-1 with two cognates, OFS-2 and OFS-3. In solution or when preadsorbed on HAp, OFS-1 exhibited strong fluorescence when exposed to Ctsk (2.5−20 nM). Time-lapse photomicrographs obtained after seeding human osteoclasts onto HAp-coated well plates containing preadsorbed OFS-1 revealed bright fluorescence at the periphery of resorbing cells. OFS-1 administered systemically detected early osteolysis colocalized with orthotopic engraftment of RPMI-8226-Luc human multiple myeloma cells at a metastatic skeletal site in a humanized mouse model. OFS-1 is thus a promising new imaging tool for detecting abnormal bone resorption.

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“…Prefers an aromatic or aliphatic residue and tolerates a basic P2, an aromatic residue in P1 and a P3 G [127] Influenza A virus [135], Mammalian Orthoreovirus [132], Nipah [124], SARS-CoV-2 [136] Cathepsin S Prefers aliphatic residues in P2, G/E in P1 [127] Mammalian Orthoreovirus [137], SARS-CoV-2, SARS-CoV-1, RSV [52] Cathepsin W W/F-L/V-G/A/R↓V-D/N/E/Q (suggested [138]) Influenza A virus [139], RSV [52] Cathepsin K Prefers non-aromatic hydrophobic residues in P2 [140] SARS-CoV-2 [136] Cathepsin V Prefers hydrophobic residues in P2, P in P3 [141] SARS-CoV-2 [136]…”

Section: Cysteine Proteases Cleavage Determinants Exploiting Respirat...mentioning

confidence: 99%

Host Cell Proteases Involved in Human Respiratory Viral Infections and Their Inhibitors: A Review

Lubinski,

Whittaker

2024

Viruses

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Viral tropism is most commonly linked to receptor use, but host cell protease use can be a notable factor in susceptibility to infection. Here we review the use of host cell proteases by human viruses, focusing on those with primarily respiratory tropism, particularly SARS-CoV-2. We first describe the various classes of proteases present in the respiratory tract, as well as elsewhere in the body, and incorporate the targeting of these proteases as therapeutic drugs for use in humans. Host cell proteases are also linked to the systemic spread of viruses and play important roles outside of the respiratory tract; therefore, we address how proteases affect viruses across the spectrum of infections that can occur in humans, intending to understand the extrapulmonary spread of SARS-CoV-2.

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Cathepsin K

Cited by 6 publications

References 76 publications

A redox-shifted fibroblast subpopulation emerges in the fibrotic lung

A redox-shifted fibroblast subpopulation emerges in the fibrotic lung

Design and Synthesis of Cathepsin-K-Activated Osteoadsorptive Fluorogenic Sentinel (OFS) Probes for Detecting Early Osteoclastic Bone Resorption in a Multiple Myeloma Mouse Model

Host Cell Proteases Involved in Human Respiratory Viral Infections and Their Inhibitors: A Review

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