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RNA-seq analysis of osteogenic differentiating mouse wild type (WT) and Zfp384 (Nmp4) knockout mesenchymal stem/progenitor cells (MSPCs)

ABSTRACT: A goal of osteoporosis therapy is to restore lost bone with structurally sound tissue. Mice lacking the transcription factor Nmp4 respond to several classes of osteoporosis drugs with enhanced bone formation compared to wild type (WT) animals. To address how loss of Nmp4 maximizes anabolic output we used RNA-seq and network analyses, along with biochemical and bone mechanical measurements to define this anti-anabolic axis. Several independent preparations of expanded mesenchymal stem/progenitor cells (MSPCs) were derived from individual Nmp4-/- and WT mice. The Nmp4-/- cells exhibited accelerated and enhanced mineralization. Loss of Nmp4 significantly altered the expression of over 5,000 genes. While Nmp4 status did not alter the mRNA expression of Runx2 and Sp7, key regulators of osteoblast differentiation, Nmp4-depletion enhanced expression of genes that drive osteogenesis and conversion to aerobic glycolysis, a key step in bone anabolism. Functional studies confirmed that Nmp4-/- MSPCs exhibited an enhanced capacity for glycolytic conversion. Several canonical pathways sensitive to Nmp4 status controlled protein production and delivery and as predicted the 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. Mechanical analysis of femurs from Nmp4-/- mice treated with osteoporosis therapies resulted in enhanced bone material properties compared to WT mice. In conclusion, disabling Nmp4 converts the osteoblast into a super-secretor by metabolically reprogramming the cell to support the concomitant elevated matrix production and expansion of the cell’s delivery capacity. Resolving this pathway will guide advances in osteoporosis therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE112694 | GEO | 2018/04/05

REPOSITORIES: GEO

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Project description:This a model from the article: Mathematical model of paracrine interactions between osteoclasts and osteoblasts predicts anabolic action of parathyroid hormone on bone. Komarova SV. Endocrinology.2005 Aug;146(8):3589-95. 15860557, Abstract: To restore falling plasma calcium levels, PTH promotes calcium liberation from bone. PTH targets bone-forming cells, osteoblasts, to increase expression of the cytokine receptor activator of nuclear factor kappaB ligand (RANKL), which then stimulates osteoclastic bone resorption. Intriguingly, whereas continuous administration of PTH decreases bone mass, intermittent PTH has an anabolic effect on bone, which was proposed to arise from direct effects of PTH on osteoblastic bone formation. However, antiresorptive therapies impair the ability of PTH to increase bone mass, indicating a complex role for osteoclasts in the process. We developed a mathematical model that describes the actions of PTH at a single site of bone remodeling, where osteoclasts and osteoblasts are regulated by local autocrine and paracrine factors. It was assumed that PTH acts only to increase the production of RANKL by osteoblasts. As a result, PTH stimulated osteoclasts upon application, followed by compensatory osteoblast activation due to the coupling of osteoblasts to osteoclasts through local paracrine factors. Continuous PTH administration resulted in net bone loss, because bone resorption preceded bone formation at all times. In contrast, over a wide range of model parameters, short application of PTH resulted in a net increase in bone mass, because osteoclasts were rapidly removed upon PTH withdrawal, enabling osteoblasts to rebuild the bone. In excellent agreement with experimental findings, increase in the rate of osteoclast death abolished the anabolic effect of PTH on bone. This study presents an original concept for the regulation of bone remodeling by PTH, currently the only approved anabolic treatment for osteoporosis. The model reproduces Figures 1B and 2A of the reference publication. To obtain the figures 1B, the parameter g21 needs changes. To obtain the figures 1A, the parameters g21, g12 and k2 need to changed. For details look at the curation tab. The initial concentration of Osteoclasts (x1) is corrected to 1.06066 from 10.06066. This model was taken from the CellML repository and automatically converted to SBML. The original model was: CellMLdetails The original CellML model was created by: Lloyd, Catherine, May c.lloyd@auckland.ac.nz The University of Auckland The Bioengineering Institute This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. For more information see the terms of use. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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RNA-seq analysis of osteogenic differentiating mouse wild type (WT) and Zfp384 (Nmp4) knockout mesenchymal stem/progenitor cells (MSPCs)

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