Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality

Yu Shao, Emily Wichern, Paul J. Childress, Michele Adaway, Jagannath Misra, Angela Klunk, David Burr, Ronald Wek, Amber Mosley, Yunlong Liu, Alexander Robling, Nikolai Broustovetski, James Hamilton, Kylie Jacobs, Deepak Vashishth, Keith R. Stayrook, Matthew Allen, Joseph M. Wallace, Joseph Bidwell

Research output: Contribution to journalArticle

Abstract

A 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 with 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 hyperanabolic 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. The expression of matrix genes that contribute to bone material-level mechanical properties was 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.

Original languageEnglish (US)
Pages (from-to)E749-E772
JournalAmerican journal of physiology. Endocrinology and metabolism
Volume316
Issue number5
DOIs
StatePublished - May 1 2019

Fingerprint

Mesenchymal Stromal Cells
Bone and Bones
Osteoblasts
Osteogenesis
Osteoporosis
Nuclear Matrix-Associated Proteins
RNA Sequence Analysis
Wild Animals
Glycolysis
Transcriptome
Transcription Factors
Collagen
Observation
Phenotype
Gene Expression
Pharmaceutical Preparations
Genes
Proteins

Keywords

  • bone biomechanics
  • metabolism
  • osteoporosis
  • parathyroid hormone
  • transcriptome

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality. / Shao, Yu; Wichern, Emily; Childress, Paul J.; Adaway, Michele; Misra, Jagannath; Klunk, Angela; Burr, David; Wek, Ronald; Mosley, Amber; Liu, Yunlong; Robling, Alexander; Broustovetski, Nikolai; Hamilton, James; Jacobs, Kylie; Vashishth, Deepak; Stayrook, Keith R.; Allen, Matthew; Wallace, Joseph M.; Bidwell, Joseph.

In: American journal of physiology. Endocrinology and metabolism, Vol. 316, No. 5, 01.05.2019, p. E749-E772.

Research output: Contribution to journalArticle

Shao, Y, Wichern, E, Childress, PJ, Adaway, M, Misra, J, Klunk, A, Burr, D, Wek, R, Mosley, A, Liu, Y, Robling, A, Broustovetski, N, Hamilton, J, Jacobs, K, Vashishth, D, Stayrook, KR, Allen, M, Wallace, JM & Bidwell, J 2019, 'Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality', American journal of physiology. Endocrinology and metabolism, vol. 316, no. 5, pp. E749-E772. https://doi.org/10.1152/ajpendo.00343.2018
Shao, Yu ; Wichern, Emily ; Childress, Paul J. ; Adaway, Michele ; Misra, Jagannath ; Klunk, Angela ; Burr, David ; Wek, Ronald ; Mosley, Amber ; Liu, Yunlong ; Robling, Alexander ; Broustovetski, Nikolai ; Hamilton, James ; Jacobs, Kylie ; Vashishth, Deepak ; Stayrook, Keith R. ; Allen, Matthew ; Wallace, Joseph M. ; Bidwell, Joseph. / Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality. In: American journal of physiology. Endocrinology and metabolism. 2019 ; Vol. 316, No. 5. pp. E749-E772.
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abstract = "A 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 with 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 hyperanabolic 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. The expression of matrix genes that contribute to bone material-level mechanical properties was 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.",
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AU - Broustovetski, Nikolai

AU - Hamilton, James

AU - Jacobs, Kylie

AU - Vashishth, Deepak

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AU - Allen, Matthew

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