Work

TNAP and PHOSPHO1 Function Synergistically to Afford Critical Control Over the Mineralization of the Postnatal Murine Skeleton

Year: 2026

Type: article

Abstract: ABSTRACT Biomineralization is essential for skeletal integrity, yet the synergistic roles of tissue non‐specific alkaline phosphatase (TNAP) and PHOSPHO1 in postnatal bone remain unclear. We generated a novel murine model with Prx1 ‐driven deletion of Alpl ( Alpl Prx1/Prx1 ) on a global Phospho1 −/− background, circumventing the perinatal lethality associated with dual global deletion and premature death of Alpl global knockouts. Multi‐modal spatial phenotyping of the limbs revealed that mice lacking both TNAP and PHOSPHO1 exhibit distinct mineralization defects and altered anatomical structures at postnatal day 1 (PN1) and 3‐weeks of age. Although viable, these mice did not thrive due to reduced size; thus further investigations were conducted on mice with heterozygous deletion of TNAP ( Alpl wt/Prx1 ;Phospho1 −/− ). Although smaller than wild‐types at PN1 and 3 weeks old, these mice preserved gross limb structure and the single, functioning Alpl allele rescued biomineralization loss following dual phosphatase deletion. In 6‐week animals, compromised epiphyses and metaphyses were only observed in Alpl Prx1/Prx1 animals. Conversely, diaphyseal geometry and porosity were altered by Phospho1 deletion, compounded in Alpl wt/Prx1 ;Phospho1 −/‒ mice, and linked to alterations in collagen configuration, matrix mineralization, and growth plate deformities. Together, our findings support a mechanistic framework for TNAP and PHOSPHO1 in permissive biomineralization, providing critical insights into this fundamental process.

Source: Advanced Science

DOI: 10.1002/advs.77671