Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 01, 2019
- Source ID
- 10.1152/ajpendo.00343.2018
Entities
People
- Alexander G. Robling
- Amber L. Mosley
- Angela Klunk
- David B. Burr
- Deepak Vashishth
- Emily Wichern
- Jagannath Misra
- James M. Hamilton
- Joseph M. Wallace
- Joseph P. Bidwell
- Keith R. Stayrook
- Kylie Jacobs
- Matthew R. Allen
- Michele Adaway
- Nickolay Brustovetsky
- Paul J. Childress
- Ronald C. Wek
- Yu Shao
- Yunlong Liu
Organizations
- Eli Lilly and Company
- Indiana University
- Indiana University – Purdue University Indianapolis
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Institute of General Medical Sciences
- National Institutes of Health
- Rensselaer Polytechnic Institute
- United States Department of Defense