NFATc1 Is Required for Vitamin D- and Phosphate-Mediated Regulation of Osteocyte Lacuno-Canalicular Remodeling.

Authors

Supriya Jagga
Ashleigh Hughes
Niusha Manoochehri Arash
Melissa Sorsby
Daniel J Brooks
Paola Divieti Pajevic
Eva S Liu

Language

English

Publication Date

7-1-2024

Journal

Endocrinology

DOI

10.1210/endocr/bqae087

PMID

39024412

PMCID

PMC11492278

PubMedCentral® Posted Date

7-18-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Osteocytes are embedded in lacunae and connected by canaliculi (lacuno-canalicular network, LCN). Bones from mice with X-linked hypophosphatemia (Hyp), which have impaired production of 1,25 dihydroxyvitamin D (1,25D) and hypophosphatemia, have abnormal LCN structure that is improved by treatment with 1,25D or an anti-FGF23 targeting antibody, supporting roles for 1,25D and phosphate in regulating LCN remodeling. Bones from mice lacking the vitamin D receptor (VDR) in osteocytes (Vdrf/f;Dmp1Cre+) and mice lacking the sodium phosphate transporter 2a (Npt2aKO), which have low serum phosphate with high serum 1,25D, have impaired LCN organization, demonstrating that osteocyte-specific actions of 1,25D and hypophosphatemia regulate LCN remodeling. In osteoclasts, nuclear factor of activated T cells cytoplasmic 1 (NFATc1) is critical for stimulating bone resorption. Since osteocytes also resorb matrix, we hypothesize that NFATc1 plays a role in 1,25D and phosphate-mediated LCN remodeling. Consistent with this, 1,25D and phosphate suppress Nfatc1 mRNA expression in IDG-SW3 osteocytes, and knockdown of Nfatc1 expression in IDG-SW3 cells blocks 1,25D- and phosphate-mediated suppression of matrix resorption gene expression and 1,25D- and phosphate-mediated suppression of RANKL-induced acidification of the osteocyte microenvironment. To determine the role of NFATc1 in 1,25D- and phosphate-mediated LCN remodeling in vivo, histomorphometric analyses of tibiae from mice lacking osteocyte-specific Nfatc1 in Vdrf/f;Dmp1Cre+ and Npt2aKO mice were performed, demonstrating that bones from these mice have decreased lacunar size and expression of matrix resorption genes, and improved canalicular structure compared to Vdrf/f;Dmp1Cre+ and Npt2aKO control. This study demonstrates that NFATc1 is necessary for 1,25D- and phosphate-mediated regulation of LCN remodeling.

Keywords

Animals, Male, Mice, Bone Remodeling, Familial Hypophosphatemic Rickets, Fibroblast Growth Factor-23, Mice, Inbred C57BL, Mice, Knockout, NFATC Transcription Factors, Osteocytes, Phosphates, Receptors, Calcitriol, Sodium-Phosphate Cotransporter Proteins, Type IIa, Vitamin D, Female

Published Open-Access

yes

Recommended Citation

Jagga, Supriya; Hughes, Ashleigh; Manoochehri Arash, Niusha; et al., "NFATc1 Is Required for Vitamin D- and Phosphate-Mediated Regulation of Osteocyte Lacuno-Canalicular Remodeling." (2024). Staff and Researcher Publications. 2.
https://digitalcommons.library.tmc.edu/clinic_pub/2