Chondroitin Sulfate Promotes Activation of Cathepsin K

Lemaire, Peter A.; Huang, Lingyi; Zhuo, Ya; Lü, Jun; Bahnck, Carolyn; Stachel, Shawn J.; Carroll, Steve; Duong, Le T.

doi:10.1074/jbc.m114.559898

Cited by 22 publications

(17 citation statements)

References 48 publications

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“…Inhibiting TGF-β signaling in either wild-type (WT) or MLII embryos impaired Ctsk processing, reducing its activity. TGF-β mediates its effect on Ctsk by increasing expression of the primary sulfotransferase ( chst11 ) that generates chondroitin 4-sulfate (C4-S), a known Ctsk modulator ( Lemaire et al, 2014 ; Li et al, 2000 , 2004 ). This work identifies a regulatory loop between cathepsins and TGF-β signaling in developing cartilage that is disrupted when lysosomal targeting is impaired.…”

Section: Introductionmentioning

confidence: 99%

TGF-ß Regulates Cathepsin Activation during Normal and Pathogenic Development

Flanagan-Steet

Christian

et al. 2018

Cell Reports

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SUMMARY Cysteine cathepsins play roles during development and disease beyond their function in lysosomal protein turnover. Here, we leverage a fluorescent activity-based probe (ABP), BMV109, to track cysteine cathepsins in normal and diseased zebrafish embryos. Using this probe in a model of mucolipidosis II, we show that loss of carbohydrate-dependent lysosomal sorting alters the activity of several cathepsin proteases. The data support a pathogenic mechanism where TGF-β signals enhance the proteolytic processing of pro-Ctsk by modulating the expression of chondroitin 4-sulfate (C4-S). In MLII, elevated C4-S corresponds with TGF-β-mediated increases in chst11 expression. Inhibiting chst11 impairs the proteolytic activation of Ctsk and alleviates the MLII phenotypes. These findings uncover a regulatory loop between TGF-β signaling and Ctsk activation that is altered in the context of lysosomal disease. This work highlights the power of ABPs to identify mechanisms underlying pathogenic development in living animals.

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Section: Introductionmentioning

confidence: 99%

TGF-ß Regulates Cathepsin Activation during Normal and Pathogenic Development

Flanagan-Steet

Christian

et al. 2018

Cell Reports

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“…d ‐GalNAc may contain a 6‐ O ‐sulfate group (CS‐C) or/and a 4‐ O ‐sulfate group (CS‐A/CS‐E), and d ‐GlcA may be sulfated at the 2‐ O or 3‐ O position, thus leading to a huge diversity in the CS sequence (Scheme ) . In addition to its well‐known structural function in the extracellular matrix, major biological roles have been recently highlighted in cellular communication and development . Being present in the brain, articulations, placenta, and immune system, CS plays a critical role in various physio‐pathological processes .…”

Section: Introductionmentioning

confidence: 99%

Isomer separation and effect of the degree of polymerization on the gas‐phase structure of chondroitin sulfate oligosaccharides analyzed by ion mobility and tandem mass spectrometry

Poyer

Lopin‐Bon

Jacquinet

et al. 2017

Rapid Comm Mass Spectrometry

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“…Since CtsK is activated directly by chondroitin sulfate [47], a GAG that accumulates in MPS VII, it may be activated independently of signaling pathways. Indeed, CtsK mRNA and/or enzyme activity were elevated in the annulus fibrosus of the spine of MPS VII dogs [6] and in the aorta of MPS VII mice [27].…”

Section: Discussionmentioning

confidence: 99%

The effect of Tlr4 and/or C3 deficiency and of neonatal gene therapy on skeletal disease in mucopolysaccharidosis VII mice

Xing

Ponder

2015

Molecular Genetics and Metabolism

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Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder caused by the deficiency of the enzyme β-glucuronidase (Gusb-/-) and results in glycosaminoglycan (GAG) accumulation. Skeletal abnormalities include stunted long bones and bone degeneration. GAGs have been hypothesized to activate toll-like receptor 4 (Tlr4) signaling and the complement pathway, resulting in upregulation of inflammatory cytokines that suppress growth and cause degeneration of bone. Gusb-/- mice were bred with Tlr4- and complement component 3 (C3)-deficient mice, and the skeletal manifestations of the doubly- and triply-deficient mice were compared to those of purebred Gusb-/- mice. Radiographs showed that purebred Gusb-/- mice had shorter tibias and femurs, and wider femurs, compared to normal mice. No improvement was seen in Tlr4, C3, or Tlr4/C3-deficient Gusb-/- mice. The glenoid cavity and humerus were scored on a scale from 0 (normal) to +3 (severely abnormal) for dysplasia and bone irregularities, and the joint space was measured. No improvement was seen in Tlr4, C3, or Tlr4/C3-deficient Gusb-/- mice, and their joint space remained abnormally wide. Gusb-/- mice treated neonatally with an intravenous retroviral vector (RV) had thinner femurs, longer legs, and a narrowed joint space compared with untreated purebred Gusb-/- mice, but no improvement in glenohumeral degeneration. We conclude that Tlr4- and/or C3- deficiency fail to ameliorate skeletal abnormalities, and other pathways may be involved. RV treatment improves some but not all aspects of bone disease. Radiographs may be an efficient method for future evaluation, as they readily show glenohumeral joint abnormalities.

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Chondroitin Sulfate Promotes Activation of Cathepsin K

Cited by 22 publications

References 48 publications

TGF-ß Regulates Cathepsin Activation during Normal and Pathogenic Development

TGF-ß Regulates Cathepsin Activation during Normal and Pathogenic Development

Isomer separation and effect of the degree of polymerization on the gas‐phase structure of chondroitin sulfate oligosaccharides analyzed by ion mobility and tandem mass spectrometry

The effect of Tlr4 and/or C3 deficiency and of neonatal gene therapy on skeletal disease in mucopolysaccharidosis VII mice

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