ArticleThe Journal of biological chemistry2014
Low density lipoprotein receptor-related protein 1 (LRP1)-mediated endocytic clearance of a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4): functional differences of non-catalytic domains of ADAMTS-4 and ADAMTS-5 in LRP1 binding.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 86 citations in OpenAlex.
- The activity "blind spot": Why understanding which proteinases are active, not merely present, is essential for rigorous osteoarthritis research.Osteoarthritis and cartilage · 2026Review
- Avenanthramide C and chondroitin sulphate promote chondrogenic differentiation of adipose-derived mesenchymal stem cells.Scientific reports · 2026Article
- The ADAMTS family: from extracellular matrix proteases to orchestrators of fibrosis.Cell communication and signaling : CCS · 2026Review
- ADAMTS4 is expressed in different cells and tissues in leprosy skin lesions: A potential biomarker and therapeutic target for leprosy and its reactional phenomena.Histology and histopathology · 2026Article
- Article
- LRP1 Mediates Endocytosis Activity and Is a Potential Therapeutic Target in Osteoarthritis.Orthopaedic surgery · 2025Review
- Skeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulation.Bone research · 2025Article
- LRP1 mitigates intervertebral disc degeneration by inhibiting endoplasmic reticulum stress through stabilizing the PPARγ.Journal of orthopaedic translation · 2025Article
- Article
- Novel insights into the multifaceted and tissue-specific roles of the endocytic receptor LRP1.The Journal of biological chemistry · 2024Review
- ADAMTS4 is a crucial proteolytic enzyme for versican cleavage in the amnion at parturition.Communications biology · 2024Article
- Phylogenetic inference of the emergence of sequence modules and protein-protein interactions in the ADAMTS-TSL family.PLoS computational biology · 2023Article
- Thymosin β4 preserves vascular smooth muscle phenotype in atherosclerosis via regulation of low density lipoprotein related protein 1 (LRP1).International immunopharmacology · 2023Article
- Review
- Cell surface nucleolin is a novel ADAMTS5 receptor mediating endothelial cell apoptosis.Cell death & disease · 2022Article
- The Biology and Function of Tissue Inhibitor of Metalloproteinase 2 in the Lungs.Pulmonary medicine · 2022Review
- ADAMTS Proteins and Vascular Remodeling in Aortic Aneurysms.Biomolecules · 2021Review
- Targeting Dysregulation of Metalloproteinase Activity in Osteoarthritis.Calcified tissue international · 2021Review
- Serpins in cartilage and osteoarthritis: what do we know?Biochemical Society transactions · 2021Review
- Strategies to Target ADAM17 in Disease: From its Discovery to the iRhom Revolution.Molecules (Basel, Switzerland) · 2021Review
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Authors and funding
8 authors at 5 institutions in 2 countries.
Funding
Abstract
Degradation of the cartilage proteoglycan aggrecan is an early event in the development of osteoarthritis, and a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are considered to be the major aggrecan-degrading enzymes. We have recently found that ADAMTS-5 is rapidly endocytosed via low density lipoprotein receptor-related protein 1 (LRP1) and degraded by chondrocytes. Here we report that this regulatory mechanism also applies to ADAMTS-4, although its rate of endocytosis is slower than that of ADAMTS-5. Domain deletion mutagenesis of ADAMTS-4 identified that the cysteine-rich and spacer domains are responsible for binding to LRP1, whereas the thrombospondin 1 and spacer domains are responsible in ADAMTS-5. The estimated t½ value of ADAMTS-4 endocytosis was about 220 min, whereas that of ADAMTS-5 was 100 min. The difference in half-lives between the two enzymes is explained by the 13-fold lower affinity of ADAMTS-4 for LRP1 compared with that of ADAMTS-5. Studies using soluble ligand binding clusters of LRP1 showed that ADAMTS-4 binds to clusters II and IV with similar KD,app values of 98 and 73 nm, respectively, whereas ADAMTS-5 binds to cluster II, III, and IV with KD,app values of 3.5, 41, and 9 nm, respectively. Thus, ADAMTS-5 competitively inhibits ADAMTS-4 endocytosis but not vice versa. This study highlights that the affinity between a ligand and LRP1 dictates the rate of internalization and suggests that LRP1 is a major traffic controller of the two aggrecanases, especially under inflammatory conditions, where the protein levels of ADAMTS-4 increase, but those of ADAMTS-5 do not.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.