Childress, PaulStayrook, Keith R.Alvarez, Marta B.Wang, ZhipingShao, YuHernandez-Buquer, SeleneMack, Justin K.Grese, Zachary R.He, YongzhengHoran, DanielPavalko, Fredrick M.Warden, Stuart J.Robling, Alexander G.Yang, Feng-ChunAllen, Matthew R.Krishnan, VenkateshLiu, YunlongBidwell, Joseph P.2017-05-222017-05-222015-09Childress, P., Stayrook, K. R., Alvarez, M. B., Wang, Z., Shao, Y., Hernandez-Buquer, S., … Bidwell, J. P. (2015). Genome-Wide Mapping and Interrogation of the Nmp4 Antianabolic Bone Axis. Molecular Endocrinology, 29(9), 1269–1285. http://doi.org/10.1210/me.2014-1406https://hdl.handle.net/1805/12667PTH 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 on Nmp4 chromatin 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. Ovx Nmp4(-/-) 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 target genes likely under Nmp4 control as enriched for negative regulators of biosynthetic processes. Interrogation of mRNA transcripts 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.Publisher PolicyBone densityBone diseasesPTHOsteoanabolicsOsteoporosisOsteoprogenitorsArticle