Impaired 1,25 dihydroxyvitamin D.sub.3 action and hypophosphatemia underlie the altered lacuno-canalicular remodeling observed in the Hyp mouse model of XLH

• Published in: PloS one 2021-05, Vol.16 (5), p.e0252348
• Main Authors: Yuan, Ye, Jagga, Supriya, Martins, Janaina S, Rana, Rakshya, Pajevic, Paola Divieti, Liu, Eva S
• Format: Article
• Language: English
• Subjects: Analysis; Bone cells; Complications and side effects; Hypophosphatemia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0252348

Osteocytes remodel the perilacunar matrix and canaliculi. X-linked hypophosphatemia (XLH) is characterized by elevated serum levels of fibroblast growth factor 23 (FGF23), leading to decreased 1,25 dihydroxyvitamin D.sub.3 (1,25D) production and hypophosphatemia. Bones from mice with XLH (Hyp) have enlarged osteocyte lacunae, enhanced osteocyte expression of genes of bone remodeling, and impaired canalicular structure. The altered lacuno-canalicular (LCN) phenotype is improved with 1,25D or anti-FGF23 antibody treatment, pointing to roles for 1,25D and/or phosphate in regulating this process. To address whether impaired 1,25D action results in LCN alterations, the LCN phenotype was characterized in mice lacking the vitamin D receptor (VDR) in osteocytes (VDR.sup.f/f;DMP1Cre+). Mice lacking the sodium phosphate transporter NPT2a (NPT2aKO) have hypophosphatemia and high serum 1,25D levels, therefore the LCN phenotype was characterized in these mice to determine if increased 1,25D compensates for hypophosphatemia in regulating LCN remodeling. Unlike Hyp mice, neither VDR.sup.f/f;DMP1Cre+ nor NPT2aKO mice have dramatic alterations in cortical microarchitecture, allowing for dissecting 1,25D and phosphate specific effects on LCN remodeling in tibial cortices. Histomorphometric analyses demonstrate that, like Hyp mice, tibiae and calvariae in VDR.sup.f/f;DMP1Cre+ and NPT2aKO mice have enlarged osteocyte lacunae (tibiae: 0.15±0.02[mu]m.sup.2 (VDR.sup.f/f;DMP1Cre-) vs 0.19±0.02[mu]m.sup.2 (VDR.sup.f/f;DMP1Cre+ ), 0.12±0.02[mu]m.sup.2 (WT) vs 0.18±0.0[mu]m.sup.2 (NPT2aKO), calvariae: 0.09±0.02[mu]m.sup.2 (VDR.sup.f/f;DMP1Cre-) vs 0.11±0.02[mu]m.sup.2 (VDR.sup.f/f;DMP1Cre+ ), 0.08±0.02[mu]m.sup.2 (WT) vs 0.13±0.02[mu]m.sup.2 (NPT2aKO), p