| First Author | Shao Y | Year | 2019 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 316 |
| Issue | 5 | Pages | E749-E772 |
| PubMed ID | 30645175 | Mgi Jnum | J:274687 |
| Mgi Id | MGI:6303404 | Doi | 10.1152/ajpendo.00343.2018 |
| Citation | Shao Y, et al. (2019) Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality. Am J Physiol Endocrinol Metab 316(5):E749-E772 |
| abstractText | 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. |
