Post-translational regulation and proteolytic activity of the metalloproteinase ADAMTS8

Santamaria, Salvatore; Martin, Daniel R.; Dong, Xingchen; Yamamoto, Kazuhiro; Apte, Suneel S.; Ahnström, Josefin

doi:10.1016/j.jbc.2021.101323

Cited by 20 publications

(20 citation statements)

References 74 publications

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“…On the basis of sequence homology, ADAMTS1 has been assigned to a subgroup of ADAMTS proteases comprising so called proteoglycanases (ADAMTS4, 5, 8, 9, 15, and 20), whose members have been reported to share the ability to cleave chondroitin sulfate proteoglycans ( 20 ) (although we have recently shown that ADAMTS8 shows negligible proteoglycanase activity in vitro ( 21 )). Proteoglycans are highly decorated with glycosaminoglycans (GAGs) and represent major structural components of the extracellular matrix (ECM).…”

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confidence: 99%

The C-terminal domains of ADAMTS1 contain exosites involved in its proteoglycanase activity

Minns¹,

Qi²,

Yamamoto³

et al. 2023

Journal of Biological Chemistry

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confidence: 99%

The C-terminal domains of ADAMTS1 contain exosites involved in its proteoglycanase activity

Minns¹,

Qi²,

Yamamoto³

et al. 2023

Journal of Biological Chemistry

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“…Proteolytic degradation by LRP1 ligands is thus likely to contribute to reduction of the number of secreted proteins in particular ECM molecules. Indeed, levels of versican, nidogen-2 and biglycan, all previously reported substrates for ADAMTS1 [67][68][69], were reduced in the medium of chondrocytes treated with sLRP1-II (Table II).…”

Section: Discussionmentioning

confidence: 68%

Uncovering the ligandome of low-density lipoprotein receptor-related protein 1 in cartilage: a top-down approach to identify therapeutic targets

Yamamoto

Scavenius

Meschis

et al. 2022

Preprint

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The low-density lipoprotein receptor-related protein 1 (LRP1) is a cell-surface receptor ubiquitously expressed in adult tissues. It plays tissue-specific physiological roles by mediating endocytosis of a diverse range of extracellular molecules. Dysregulation of LRP1 is involved in multiple conditions including Alzheimer′s disease, atherosclerosis and osteoarthritis (OA). However, little information is available about the specific ligand profile (ligandome) for each tissue, which would lead to better understanding of its role in disease states. Here, we investigated adult articular cartilage where impaired LRP1-mediated endocytosis leads to tissue destruction. We used a top-down approach involving analysis of human chondrocyte secretome, direct binding assays and validation in LRP1-deficient fibroblasts, as well as a novel Lrp1 conditional knockout (KO) mouse model. We found that inhibition of LRP1-mediated endocytosis results in cell death, alteration of the entire secretome and transcriptional modulations in human chondrocytes. We have identified more than 50 novel ligand candidates and confirmed direct LRP1 binding of HGFAC, HMGB1, HMGB2, CEMIP, SLIT2, ADAMTS1, IGFBP7, SPARC and LIF. Our in vitro endocytosis assay revealed the correlation of their affinity for LRP1 and the rate of endocytosis. Moreover, a conditional LRP1 KO mouse model demonstrated a critical role of LRP1 in regulating the high-affinity ligands in cartilage in vivo. This systematic approach revealed the extent of the chondrocyte LRP1 ligandome and identified potential novel therapeutic targets for OA.

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Section: Discussionmentioning

confidence: 99%

“…Targeted deletion of Adamts8 in myocytes and vSMCs of pulmonary arteries in mice has been associated with reduced right ventricular hypertrophy and systolic pressure, compared to wild type controls, when subjected to hypoxia-induced PAH. 40 Although concluded to be an inefficient aggrecanase, ADAMTS8 cleaves osteopontin, 39 a phosphoprotein that is increased in plasma of patients with PAH and that correlates with disease severity and mortality. 41 Combining RNAscope in situ hybridization for ACAN with immunofluorescence revealed that aggrecan in hypertrophic tunica media was locally produced in the lesion, mainly by what we suggest are vSMCs, and in intimal lesions and plexiform lesions, primarily in regions positive for vWF or Claudin 5.…”

Section: Discussionmentioning

confidence: 99%

Aggrecan accumulates at sites of increased pulmonary arterial pressure in idiopathic pulmonary arterial hypertension

et al. 2023

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Expansion of extracellular matrix occurs in all stages of pulmonary angiopathy associated with pulmonary arterial hypertension (PAH). In systemic arteries, dysregulation and accumulation of the large chondroitin‐sulfate proteoglycan aggrecan is associated with swelling and disruption of vessel wall homeostasis. Whether aggrecan is present in pulmonary arteries, and its potential roles in PAH, has not been thoroughly investigated. Here, lung tissue from 11 patients with idiopathic PAH was imaged using synchrotron radiation phase‐contrast microcomputed tomography (TOMCAT beamline, Swiss Light Source). Immunohistochemistry for aggrecan core protein in subsequently sectioned lung tissue demonstrated accumulation in PAH compared with failed donor lung controls. RNAscope in situ hybridization indicated ACAN expression in vascular endothelium and smooth muscle cells. Based on qualitative histological analysis, aggrecan localizes to cellular, rather than fibrotic or collagenous, lesions. Interestingly, ADAMTS15 , a potential aggrecanase, was upregulated in pulmonary arteries in PAH. Aligning traditional histological analysis with three‐dimensional renderings of pulmonary arteries from synchrotron imaging identified aggrecan in lumen‐reducing lesions containing loose, cell‐rich connective tissue, at sites of intrapulmonary bronchopulmonary shunting, and at sites of presumed elevated pulmonary blood pressure. Our findings suggest that ACAN expression may be an early response to injury in pulmonary angiopathy and supports recent work showing that dysregulation of aggrecan turnover is a hallmark of arterial adaptations to altered hemodynamics. Whether cause or effect, aggrecan and aggrecanase regulation in PAH are potential therapeutic targets.

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Post-translational regulation and proteolytic activity of the metalloproteinase ADAMTS8

Cited by 20 publications

References 74 publications

The C-terminal domains of ADAMTS1 contain exosites involved in its proteoglycanase activity

The C-terminal domains of ADAMTS1 contain exosites involved in its proteoglycanase activity

Uncovering the ligandome of low-density lipoprotein receptor-related protein 1 in cartilage: a top-down approach to identify therapeutic targets

Aggrecan accumulates at sites of increased pulmonary arterial pressure in idiopathic pulmonary arterial hypertension

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