Shao, YuWichern, EmilyChildress, Paul J.Adaway, MicheleMisra, JagannathKlunk, AngelaBurr, David B.Wek, Ronald C.Mosley, Amber L.Liu, YunlongRobling, Alexander G.Brustovetsky, NickolayHamilton, JamesJacobs, KylieVashishth, DeepakStayrook, Keith R.Allen, Matthew R.Wallace, Joseph M.Bidwell, Joseph P.2019-02-152019-02-152019Shao, Y., Wichern, E., Childress, P. J., Adaway, M., Misra, J., Klunk, A., … Bidwell, J. P. (2019). Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality. American Journal of Physiology-Endocrinology and Metabolism. https://doi.org/10.1152/ajpendo.00343.2018https://hdl.handle.net/1805/18392A goal of osteoporosis therapy is to restore lost bone with structurally sound tissue. Mice lacking the transcription factor Nuclear Matrix Protein 4 (Nmp4, Zfp384, Ciz, ZNF384) respond to several classes of osteoporosis drugs with enhanced bone formation compared to wild type (WT) animals. Nmp4-/- mesenchymal stem/progenitor cells (MSPCs) exhibit an accelerated and enhanced mineralization during osteoblast differentiation. To address the mechanisms underlying this hyper-anabolic phenotype, we carried out RNA-sequencing and molecular and cellular analyses of WT and Nmp4-/- MSPCs during osteogenesis to define pathways and mechanisms associated with elevated matrix production. We determined that Nmp4 has a broad impact on the transcriptome during osteogenic differentiation, contributing to the expression of over 5,000 genes. Phenotypic anchoring of transcriptional data was performed for the hypothesis-testing arm through analysis of cell metabolism, protein synthesis and secretion, and bone material properties. Mechanistic studies confirmed that Nmp4-/- MSPCs exhibited an enhanced capacity for glycolytic conversion- a key step in bone anabolism. Nmp4-/- cells showed elevated collagen translation and secretion. Expression of matrix genes that contribute to bone material-level mechanical properties were elevated in Nmp4-/- cells, an observation that was supported by biomechanical testing of bone samples from Nmp4-/- and WT mice. We conclude that loss of Nmp4 increases the magnitude of glycolysis upon the metabolic switch, which fuels the conversion of the osteoblast into a super-secretor of matrix resulting in more bone with improvements in intrinsic quality.enPublisher Policymetabolismosteoporosisparathyroid hormoneArticle