2025/12/10 by Robbe Derudder, Olivier Vanakker · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Dermatological and Skeletal Disorders #Parathyroid Disorders and Treatments #Alkaline Phosphatase Research Studies
paper · pdf · doi:10.1002/jimd.70129
openalex publication_date 2025/12/10 · openalex created_date 2025/12/11 · openalex updated_date 2026/07/28
Pathological ectopic calcification of soft tissues can arise from reduced or absent levels of inorganic pyrophosphate (PPi), a key inhibitor of calcium hydroxyapatite deposition in soft connective tissues. The role of PPi in regulating mineralization has been recognized for decades, thanks to the pivotal work of Herbert Fleisch and colleagues; and its clinical relevance has been underscored by the identification of hereditary metabolic disorders, collectively termed PPi deficiency syndromes. These are caused by pathogenic variants in the essential genes for maintaining PPi homeostasis: ATP-binding cassette subfamily C member 6 (ABCC6), ectonucleotide pyrophosphate phosphodiesterase 1 (ENPP1), progressive ankylosis protein (ANK), tissue-nonspecific alkaline phosphatase (ALPL), CD73, and CD39. In recent years, abnormalities in lipid metabolism have been reported in these monogenic conditions. However, a common understanding of these alterations has yet to be established. This review provides an overview of the pathophysiology of PPi deficiency syndromes-pseudoxanthoma elasticum, generalized arterial calcification of infancy, arterial calcification due to CD73 deficiency, ankylosis, and Hutchinson-Gilford progeria syndrome-highlighting the lipid metabolism alterations in cells, animal models, and patients. We explore the evidence for a potential role of PPi-regulating proteins in lipid metabolic pathways to demonstrate that lipid alterations are not coincidental but entail opportunities for future research and for potential therapeutic interventions.