ArticleJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research2016
Cathepsin-Mediated Alterations in TGFß-Related Signaling Underlie Disrupted Cartilage and Bone Maturation Associated With Impaired Lysosomal Targeting.
Article in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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Who cites it
20 citing papers in PubMed, 24 citations in OpenAlex.
- Enhanced lysosomal exocytosis and altered growth factor signaling are associated with cartilage pathology in a model of mucopolysaccharidosis type IVA.Disease models & mechanisms · 2026Article
- Age-sensitive response of systemic AAV-mediated gene therapy in a newly characterized feline model of mucolipidosis II.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Unraveling the causal nexus of cathepsins and rheumatoid arthritis: Insights from a two-sample Mendelian randomization framework.Medicine · 2025Article
- O-GlcNAcylation modulates expression and abundance of N-glycosylation machinery in an inherited glycosylation disorder.Cell reports · 2024Article
- Dysregulated lysosomal exocytosis drives protease-mediated cartilage pathogenesis in multiple lysosomal disorders.iScience · 2024Article
- A tapt1 knock-out zebrafish line with aberrant lens development and impaired vision models human early-onset cataract.Human genetics · 2023Article
- Article
- Zebrafish Models for Human Skeletal Disorders.Frontiers in genetics · 2021Review
- Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation.JCI insight · 2020Article
- Mucolipidoses Overview: Past, Present, and Future.International journal of molecular sciences · 2020Review
- Deficiency in the endocytic adaptor proteins PHETA1/2 impairs renal and craniofacial development.Disease models & mechanisms · 2020Article
- Upregulation of Sortilin, a Lysosomal Sorting Receptor, Corresponds with Reduced Bioavailability of Latent TGFβ in Mucolipidosis II Cells.Biomolecules · 2020Article
- Zebrafish: A Resourceful Vertebrate Model to Investigate Skeletal Disorders.Frontiers in endocrinology · 2020Review
- Modeling Lysosomal Storage Diseases in the Zebrafish.Frontiers in molecular biosciences · 2020Review
- ClC-7 Regulates the Pattern and Early Development of Craniofacial Bone and Tooth.Theranostics · 2019Article
- Article
- Altered Met receptor phosphorylation and LRP1-mediated uptake in cells lacking carbohydrate-dependent lysosomal targeting.The Journal of biological chemistry · 2017Article
- Kinesin-1 promotes chondrocyte maintenance during skeletal morphogenesis.PLoS genetics · 2017Article
- Enzyme-specific differences in mannose phosphorylation between GlcNAc-1-phosphotransferase αβ and γ subunit deficient zebrafish support cathepsin proteases as early mediators of mucolipidosis pathology.Biochimica et biophysica acta · 2016Article
- Vertebral giant cell tumour of bone in a domestic shorthair cat.JFMS open reportsArticle
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Authors and funding
8 authors at 4 institutions in 3 countries.
Funding
Abstract
Hypersecretion of acid hydrolases is a hallmark feature of mucolipidosis II (MLII), a lysosomal storage disease caused by loss of carbohydrate-dependent lysosomal targeting. Inappropriate extracellular action of these hydrolases is proposed to contribute to skeletal pathogenesis, but the mechanisms that connect hydrolase activity to the onset of disease phenotypes remain poorly understood. Here we link extracellular cathepsin K activity to abnormal bone and cartilage development in MLII animals by demonstrating that it disrupts the balance of TGFß-related signaling during chondrogenesis. TGFß-like Smad2,3 signals are elevated and BMP-like Smad1,5,8 signals reduced in both feline and zebrafish MLII chondrocytes and osteoblasts, maintaining these cells in an immature state. Reducing either cathepsin K activity or expression of the transcriptional regulator Sox9a in MLII zebrafish significantly improved phenotypes. We further identify components of the large latent TGFß complex as novel targets of cathepsin K at neutral pH, providing a possible mechanism for enhanced Smad2,3 activation in vivo. These findings highlight the complexity of the skeletal disease associated with MLII and bring new insight to the role of secreted cathepsin proteases in cartilage development and growth factor regulation.
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Registered trials
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.