Conditional Loss of Nmp4 in Mesenchymal Stem Progenitor Cells Enhances PTH-Induced Bone Formation.

Autor: Atkinson EG; Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA., Adaway M; Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA., Horan DJ; Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.; Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA., Korff C; Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA., Klunk A; Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA., Orr AL; Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA., Ratz K; Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA., Bellido T; Department of Physiology and Cell BiologyUniversity of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA.; Central Arkansas Veterans Healthcare System, Little Rock, AR, USA., Plotkin LI; Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.; Indiana Center for Musculoskeletal Health, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA., Robling AG; Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.; Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA.; Indiana Center for Musculoskeletal Health, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA., Bidwell JP; Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.; Indiana Center for Musculoskeletal Health, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.
Jazyk: angličtina
Zdroj: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2023 Jan; Vol. 38 (1), pp. 70-85. Date of Electronic Publication: 2022 Nov 22.
DOI: 10.1002/jbmr.4732
Abstrakt: Activation of bone anabolic pathways is a fruitful approach for treating severe osteoporosis, yet FDA-approved osteoanabolics, eg, parathyroid hormone (PTH), have limited efficacy. Improving their potency is a promising strategy for maximizing bone anabolic output. Nmp4 (Nuclear Matrix Protein 4) global knockout mice exhibit enhanced PTH-induced increases in trabecular bone but display no overt baseline skeletal phenotype. Nmp4 is expressed in all tissues; therefore, to determine which cell type is responsible for driving the beneficial effects of Nmp4 inhibition, we conditionally removed this gene from cells at distinct stages of osteogenic differentiation. Nmp4-floxed (Nmp4 fl/fl ) mice were crossed with mice bearing one of three Cre drivers including (i) Prx1Cre +  to remove Nmp4 from mesenchymal stem/progenitor cells (MSPCs) in long bones; (ii) BglapCre +  targeting mature osteoblasts, and (iii) Dmp1Cre +  to disable Nmp4 in osteocytes. Virgin female Cre +  and Cre - mice (10 weeks of age) were sorted into cohorts by weight and genotype. Mice were administered daily injections of either human PTH 1-34 at 30 μg/kg or vehicle for 4 weeks or 7 weeks. Skeletal response was assessed using dual-energy X-ray absorptiometry, micro-computed tomography, bone histomorphometry, and serum analysis for remodeling markers. Nmp4 fl/fl ;Prx1Cre +  mice virtually phenocopied the global Nmp4 -/- skeleton in the femur, ie, a mild baseline phenotype but significantly enhanced PTH-induced increase in femur trabecular bone volume/total volume (BV/TV) compared with their Nmp4 fl/fl ;Prx1Cre - controls. This was not observed in the spine, where Prrx1 is not expressed. Heightened response to PTH was coincident with enhanced bone formation. Conditional loss of Nmp4 from the mature osteoblasts (Nmp4 fl/fl ;BglapCre + ) failed to increase BV/TV or enhance PTH response. However, conditional disabling of Nmp4 in osteocytes (Nmp4 fl/fl ;Dmp1Cre + ) increased BV/TV without boosting response to hormone under our experimental regimen. We conclude that Nmp4 -/- Prx1-expressing MSPCs drive the improved response to PTH therapy and that this gene has stage-specific effects on osteoanabolism. © 2022 American Society for Bone and Mineral Research (ASBMR).
(© 2022 American Society for Bone and Mineral Research (ASBMR).)
Databáze: MEDLINE
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