ORIGINAL RESEARCH article
Front. Endocrinol.
Sec. Bone Research
Volume 16 - 2025 | doi: 10.3389/fendo.2025.1566392
This article is part of the Research TopicMolecular Mechanisms and Treatment of Monogenic Skeletal DisordersView all 7 articles
Impact of the ENPP1 Mutation on Bone Mineralization and Ectopic Calcification: Evidence from In Vitro and In Vivo Models
Provisionally accepted
- 1Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- 2Department of Radiology, Shandong Rongjun General Hospital, Jinan 250013, Shandong, China, Jinan, China
- 3Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Background: Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) plays a key role in mineralization processes, and mutations in this gene are associated with various severe diseases. Clinical case reports have implicated the ENPP1 Y451C mutation in diffuse idiopathic skeletal hyperostosis patient, but its precise impact on bone mineralization and ectopic calcification remains unclear.Methods: We used bioinformatics tools and in vitro functional assays to assess the impact of the ENPP1 Y451C mutation on ENPP1 structure and enzymatic activity. Furthermore, we generated a knock-in mouse model (Enpp1Y433C) to evaluate microarchitecture or signs of ectopic calcification by Micro-CT.Results: Bioinformatics analysis and in vitro assays showed that the Y451C mutation affects the ENPP1 protein’s structure, reducing enzymatic activity by approximately 50%. We successfully generated the Enpp1Y433C knock-in mouse model. However, no significant differences were observed in body phenotype or biochemical markers in Enpp1Y433C mice at 3, 5, and 10 months, compared to wild-type controls. Similarly, no significant changes were observed in bone microarchitecture or signs of ectopic calcification.Conclusion: The ENPP1 Y451C mutation significantly reduces enzymatic activity in vitro, yet the Enpp1Y433C knock-in mouse model shows no significant abnormalities in mineralization, providing additional evidence for the pathogenicity assessment of ENPP1 Y451C variant. Given that these results are from mouse models, further studies are required to clarify its pathogenicity in humans.
Keywords: Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), bone mineralization, ectopic calcification, Diffuse idiopathic skeletal hyperostosis, Ossification of the posterior longitudinal ligament
Received: 24 Jan 2025; Accepted: 13 May 2025.
Copyright: © 2025 Wu, Liu, Shi, Zhang, Qiu and Yan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Fang Yan, Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.