ArticleNature communications2023
The structural pathology for hypophosphatasia caused by malfunctional tissue non-specific alkaline phosphatase.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 38 citations in OpenAlex.
- Integrin αVβ3 as a context‑dependent regulator of bone homeostasis: Insights into osteoporosis pathogenesis and therapeutic targeting (Review).Molecular medicine reports · 2026Review
- Functional matrix vesicle replacement partially restores chemo-mechanical coupling in the aged bone niche.Cell reports. Medicine · 2026Article
- Hypophosphatasia: Results of a Country-Wide Selective Screening Program Using NGS Technology as a First-Tier Test.International journal of molecular sciences · 2026Article
- Article
- Identification of hypophosphatasia in adults with persistent hypophosphatasemia: clinical-genetic characterization and a validated diagnostic tool.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2026Article
- Hypophosphatasia-pathophysiological understanding, preclinical data looking beyond the skeleton, and upcoming treatments.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2026Review
- Natural history of hypophosphatasia in Chinese patients younger than 18 years: a single-center retrospective observational study.Frontiers in endocrinology · 2026Observational
- Article
- Modulation of TNAP activity and apatite formation in biomimetic matrix vesicles studied byBiochimica et biophysica acta. Biomembranes · 2025Article
- Revisiting the Genetics of Hypophosphatasia.Journal of inherited metabolic disease · 2025Review
- Genome sequencing in a cohort of 32 fetuses with genetic skeletal disorders.European journal of human genetics : EJHG · 2025Article
- TNAP dephosphorylates phosphocholine and phosphoethanolamine and participates in triglyceride transport from the liver to the bloodstream.Communications biology · 2025Article
- A novel dominant negative variant ofJBMR plus · 2025Article
- Pathophysiology of Femoral Fractures in Hypophosphatasia.Current osteoporosis reports · 2025Review
- Lifetime follow-up of an adult patient with pediatric-onset hypophosphatasia complicated with advanced chronic kidney disease.Bone reports · 2025Article
- Highly conserved brain vascular receptor ALPL mediates transport of engineered AAV vectors across the blood-brain barrier.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
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- Effects of asfotase alfa on fracture healing of adult patient with hypophosphatasia and literature review.Orphanet journal of rare diseases · 2025Review
- Efficacy of asfotase alfa in a patient with adult-onset hypophosphatasia without obvious bone lesions: a case report with review of literature.Endocrine journal · 2025Review
- Article
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hypophosphatasia (HPP) is a metabolic bone disease that manifests as developmental abnormalities in bone and dental tissues. HPP patients exhibit hypo-mineralization and osteopenia due to the deficiency or malfunction of tissue non-specific alkaline phosphatase (TNAP), which catalyzes the hydrolysis of phosphate-containing molecules outside the cells, promoting the deposition of hydroxyapatite in the extracellular matrix. Despite the identification of hundreds of pathogenic TNAP mutations, the detailed molecular pathology of HPP remains unclear. Here, to address this issue, we determine the crystal structures of human TNAP at near-atomic resolution and map the major pathogenic mutations onto the structure. Our study reveals an unexpected octameric architecture for TNAP, which is generated by the tetramerization of dimeric TNAPs, potentially stabilizing the TNAPs in the extracellular environments. Moreover, we use cryo-electron microscopy to demonstrate that the TNAP agonist antibody (JTALP001) forms a stable complex with TNAP by binding to the octameric interface. The administration of JTALP001 enhances osteoblast mineralization and promoted recombinant TNAP-rescued mineralization in TNAP knockout osteoblasts. Our findings elucidate the structural pathology of HPP and highlight the therapeutic potential of the TNAP agonist antibody for osteoblast-associated bone disorders.
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