Genome-wide mapping and interrogation of the Nmp4 antianabolic bone axis

PTH is an osteoanabolic for treating osteoporosis but its potency wanes. Disabling the transcription factor nuclear matrix protein 4 (Nmp4) in healthy, ovary-intact mice enhances bone response to PTH and bone morphogenetic protein 2 and protects from unloading-induced osteopenia. These Nmp4^-/- mice exhibit expanded bone marrow populations of osteoprogenitors and supporting CD8⁺ T cells. To determine whether the Nmp4^-/- phenotype persists in an osteoporosis model we compared PTH response in ovariectomized (ovx) wild-type (WT) and Nmp4^-/- mice. To identify potential Nmp4 target genes, we performed bioinformatic/pathway profiling onNmp4chromatin immunoprecipitation sequencing (ChIP-seq) data. Mice (12 w) were ovx or sham operated 4 weeks before the initiation of PTH therapy. Skeletal phenotype analysis included microcomputed tomography, histomorphometry, serum profiles, fluorescence- activated cell sorting and the growth/mineralization of cultured WT and Nmp4^-/- bone marrow mesenchymal stem progenitor cells (MSPCs). ChIP-seq data were derived using MC3T3-E1 preosteoblasts, murine embryonic stem cells, and 2 blood cell lines. OvxNmp4^-/- mice exhibited an improved response to PTH coupled with elevated numbers of osteoprogenitors and CD8⁺ T cells, but were not protected from ovx-induced bone loss. Cultured Nmp4^-/- MSPCs displayed enhanced proliferation and accelerated mineralization. ChIP-seq/gene ontology analyses identified targetgeneslikelyunderNmp4control as enriched for negative regulators of biosynthetic processes. Interrogation ofmRNAtranscripts in nondifferentiating and osteogenic differentiating WT and Nmp4^-/- MSPCs was performed on 90 Nmp4 target genes and differentiation markers. These data suggest that Nmp4 suppresses bone anabolism, in part, by regulating IGF-binding protein expression. Changes in Nmp4 status may lead to improvements in osteoprogenitor response to therapeutic cues.