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To decipher this, we generated a novel murine model in which\n                  <jats:italic>Alpl<\/jats:italic>\n                  was deleted in\n                  <jats:italic>Prx1<\/jats:italic>\n                  - expressing cells (\n                  <jats:italic>Alpl<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>Prx1\/Prx1<\/jats:italic>\n                  <\/jats:sup>\n                  ) in mice with a global\n                  <jats:italic>Phospho1<\/jats:italic>\n                  <jats:sup>-\/-<\/jats:sup>\n                  deficiency to overcome the perinatal lethality that arises upon dual global deletion. Using a multi-modal approach to spatially phenotype the limbs of these animals, we reveal mice lacking both TNAP and PHOSPHO1 exhibit a distinct lack of mineralisation and altered anatomical structure at postnatal day 1 (PN1) and 3-weeks of age. Although viable, these mice did not thrive due to their reduced size, thus further investigations were conducted on mice with a heterozygous deletion of TNAP (\n                  <jats:italic>Alpl<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>wt\/Prx1<\/jats:italic>\n                  <\/jats:sup>\n                  <jats:italic>;Phospho1<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>-\/-<\/jats:italic>\n                  <\/jats:sup>\n                  ). Although smaller than wild-types at PN1 and 3 weeks old, these mice did not display the gross limb deformations observed in the homozygous animals and the single, functioning\n                  <jats:italic>Alpl<\/jats:italic>\n                  allele rescued the loss of biomineralisation observed following dual phosphatase deletion. At 6-weeks of age, compromised epiphyses and metaphyses were only seen in\n                  <jats:italic>Alpl<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>Prx1\/Prx1<\/jats:italic>\n                  <\/jats:sup>\n                  animals. Further, we found that tibial geometry and porosity was significantly altered by\n                  <jats:italic>Phospho1<\/jats:italic>\n                  deletion (\n                  <jats:italic>Phospho1<\/jats:italic>\n                  <jats:sup>-\/-<\/jats:sup>\n                  ), which was compounded in the\n                  <jats:italic>Alpl<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>wt\/Prx1<\/jats:italic>\n                  <\/jats:sup>\n                  <jats:italic>;Phospho1<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>-\/-<\/jats:italic>\n                  <\/jats:sup>\n                  mice and linked to alterations in collagen configuration, matrix mineralisation and growth plate deformities. Together, our findings establish the mechanistic framework for TNAP and PHOSPHO1 in permissive biomineralisation, providing critical insights into this fundamental process.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>Biomineralisation is essential for skeletal development and is critically dependent on phosphatases that release inorganic phosphate for hydroxyapatite formation. Our study investigates the dual role of PHOSPHO1 and TNAP in this process, using a novel murine knockout model. Deletion of both enzymes results in complete loss of bone mineralisation, demonstrating their critical synergistic function. Further, we show that PHOSPHO1 and TNAP exhibit distinct, spatially-restricted functions in the tibia and thus enhances our understanding of the fundamentals processes underpinning biomineralisation. These findings also have clinical relevance as they have the potential to inform on treatment strategies for hypo- and hyper-mineralised pathologies.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.02.25.707785","type":"posted-content","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T01:45:17Z","timestamp":1772156717000},"source":"Crossref","is-referenced-by-count":0,"title":["TNAP and PHOSPHO1 function synergistically to afford critical control over the mineralisation of the postnatal murine skeleton"],"prefix":"10.64898","author":[{"given":"Lucie E","family":"Bourne","sequence":"first","affiliation":[{"name":"Centre for Lifelong Health, School of Applied Sciences, University of Brighton, Brighton, BN2 4GT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aikta","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, University College London, London, WC1E 7JE, 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