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

• Published in: American journal of physiology: endocrinology and metabolism 2019-05, Vol.316 (5), p.E749-E772
• Main Authors: Shao, Yu, Wichern, Emily, Childress, Paul J, Adaway, Michele, Misra, Jagannath, Klunk, Angela, Burr, David B, Wek, Ronald C, Mosley, Amber L, Liu, Yunlong, Robling, Alexander G, Brustovetsky, Nickolay, Hamilton, James, Jacobs, Kylie, Vashishth, Deepak, Stayrook, Keith R, Allen, Matthew R, Wallace, Joseph M, Bidwell, Joseph P
• Format: Article
• Language: English
• Subjects: Anchoring; Animals; Biocompatibility; Biomechanics; Bone growth; Bone matrix; Bone Matrix - metabolism; Calcification, Physiologic - genetics; Cells (biology); Collagen; Collagen - genetics; Collagen - metabolism; Conversion; Differentiation (biology); Gene expression; Gene Expression Profiling; Gene Expression Regulation; Gene sequencing; Genes; Glycolysis; Glycolysis - genetics; Material properties; Matrix protein; Mechanical properties; Mesenchymal Stem Cells - metabolism; Mesenchyme; Metabolism; Mice; Mice, Knockout; Mineralization; Nuclear fuels; Nuclear Matrix-Associated Proteins - genetics; Osteoblastogenesis; Osteoblasts - cytology; Osteoblasts - metabolism; Osteogenesis; Osteogenesis - genetics; Osteoporosis; Osteoporosis - metabolism; Phenotypes; Progenitor cells; Protein biosynthesis; Protein synthesis; Protein turnover; Proteins; Ribonucleic acid; RNA; RNA, Messenger - metabolism; Secretion; Stem cells; Transcription Factors - genetics
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00343.2018

A goal of osteoporosis therapy is to restore lost bone with structurally sound tissue. Mice lacking the transcription factor nuclear matrix protein 4 ( , , , ) respond to several classes of osteoporosis drugs with enhanced bone formation compared with wild-type (WT) animals. 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 MSPCs during osteogenesis to define pathways and mechanisms associated with elevated matrix production. We determined that 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 MSPCs exhibited an enhanced capacity for glycolytic conversion: a key step in bone anabolism. cells showed elevated collagen translation and secretion. The expression of matrix genes that contribute to bone material-level mechanical properties was elevated in cells, an observation that was supported by biomechanical testing of bone samples from and WT mice. We conclude that loss of 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.