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

Paul Childress, Keith R. Stayrook, Marta B. Alvarez, Zhiping Wang, Yu Shao, Selene Hernandez-Buquer, Justin K. Mack, Zachary R. Grese, Yongzheng He, Daniel Horan, Fredrick M. Pavalko, Stuart J. Warden, Alexander G. Robling, Feng Chun Yang, Matthew R. Allen, Venkatesh Krishnan, Yunlong Liu, Joseph P. Bidwell

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

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<sup>-/-</sup> mice exhibit expanded bone marrow populations of osteoprogenitors and supporting CD8<sup>+</sup> T cells. To determine whether the Nmp4<sup>-/-</sup> phenotype persists in an osteoporosis model we compared PTH response in ovariectomized (ovx) wild-type (WT) and Nmp4<sup>-/-</sup> 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<sup>-/-</sup> 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<sup>-/-</sup> mice exhibited an improved response to PTH coupled with elevated numbers of osteoprogenitors and CD8<sup>+</sup> T cells, but were not protected from ovx-induced bone loss. Cultured Nmp4<sup>-/-</sup> 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<sup>-/-</sup> 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.

Original languageEnglish (US)
Pages (from-to)1269-1285
Number of pages17
JournalMolecular Endocrinology
Volume29
Issue number9
DOIs
StatePublished - Sep 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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    Childress, P., Stayrook, K. R., Alvarez, M. B., Wang, Z., Shao, Y., Hernandez-Buquer, S., Mack, J. K., Grese, Z. R., He, Y., Horan, D., Pavalko, F. M., Warden, S. J., Robling, A. G., Yang, F. C., Allen, M. R., Krishnan, V., Liu, Y., & Bidwell, J. P. (2015). Genome-wide mapping and interrogation of the Nmp4 antianabolic bone axis. Molecular Endocrinology, 29(9), 1269-1285. https://doi.org/10.1210/me.2014-1406