Conditional Loss of Nmp4 in Mesenchymal Stem Progenitor Cells Enhances PTH‐Induced Bone Formation. (22nd November 2022)

• Record Type: Journal Article
• Authors: Atkinson, Emily G.; Adaway, Michele; Horan, Daniel J.; Korff, Crystal; Klunk, Angela; Orr, Ashley L.; Ratz, Katherine; Bellido, Teresita; Plotkin, Lilian I.; Robling, Alexander G.; Bidwell, Joseph P.
• Is Part Of: Journal of bone and mineral research. Volume 38:Number 1(2023)
• Page Start: 70
• Page End: 85
• Publication Date: 2022-11-22
• Subjects: BONE ANABOLISM -- OSTEOANABOLICS -- OSTEOPOROSIS -- TERIPARATIDE; Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.4732
• Languages: English
• ISSNs: 0884-0431

Abstract

ABSTRACT: 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).