NFI-C Regulates Osteoblast Differentiation via Control of Osterix Expression

Abstract

In bone marrow, bone marrow stromal cells (BMSCs) have the capacity to differentiate into osteoblasts and adipocytes. Age-related osteoporosis is associated with a reciprocal decrease of osteogenesis and an increase of adipogenesis in bone marrow. In this study, we demonstrate that disruption of nuclear factor I-C (NFI-C) impairs osteoblast differentiation and bone formation, and increases bone marrow adipocytes. Interestingly, NFI-C controls postnatal bone formation but does not influence prenatal bone development. We also found decreased NFI-C expression in osteogenic cells from human osteoporotic patients. Notably, transplantation of Nfic-overexpressing BMSCs stimulates osteoblast differentiation and new bone formation, but inhibits adipocyte differentiation by suppressing peroxisome proliferator-activated receptor gamma expression in Nfic 2/2 mice showing an age-related osteoporosis-like phenotype. Finally, NFI-C directly regulates Osterix expression but acts downstream of the bone morphogenetic protein-2-Runx2 pathway. These results suggest that NFI-C acts as a transcriptional switch in cell fate determination between osteoblast and adipocyte differentiation in BMSCs. Therefore, regulation of NFI-C expression in BMSCs could be a novel therapeutic approach for treating agerelated osteoporosis.

Nuclear Factor I-C (NFIC) Regulates Dentin Sialophosphoprotein (DSPP) and E-cadherin via Control of Krüppel-like Factor 4 (KLF4) During Dentinogenesis

“…It implies that miR-143 and miR-145 regulated Klf4 and Dsp via the control of Nfic, an upstream effector molecule of Klf4. Furthermore, we have shown that Nfic directly regulates Osx expression but acts downstream of the BMP2-Runx2 pathway in osteoblasts (30). These findings suggest that miR-143 and miR-145 also regulates odontoblast differentiation via the miR-143/145-NficKlf4/Osx-Dspp pathway.…”

The role of nuclear factor I-C in tooth and bone development

“…The results confirmed that Nfic promoter had a binding motif for RUNX2, and RUNX2 directly bound to that site in vitro . An in vivo study showed that Nfic expression decreased through BMP-2 pathway in Runx2 -/- mice66. Results from in vivo and in vitro studies demonstrated that Runx2 acts as an upstream regulator of Nfic .…”

Physiological mechanisms and therapeutic potential of bone mechanosensing

“…Indeed, compound heterozygous Pkd1 +/− ; Runx2 +/− mice that show additive effects to reduce bone mass, implicate Runx2 in a common pathway with PC1 [67]. Complementary in vitro studies suggest that flow induced activation the PC1-PC2 complex regulates Runx2 gene transcription through intracellular calcium and nuclear factor 1 (NFI) family of transcription proteins [67], of which Nfic has been shown to plan an essential role in inversely regulating osteoblast differentiation and bone marrow adipogenesis [169, 170]. …”