Kruppel-Like Factor 4 represses osteoblast differentiation via ciliary Hedgehog signaling.

Publisher: Academic Press Country of Publication: United States NLM ID: 0373226 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2422 (Electronic) Linking ISSN: 00144827 NLM ISO Abbreviation: Exp Cell Res Subsets: MEDLINE

Publication: Orlando Fl : Academic Press
Original Publication: New York, Academic Press.

Calcification, Physiologic/*genetics ; Cilia/*metabolism ; Hedgehog Proteins/*genetics ; Kruppel-Like Transcription Factors/*genetics ; Osteoblasts/*metabolism ; Osteogenesis/*genetics; Animals ; Animals, Newborn ; Cell Differentiation ; Cilia/genetics ; Cyclohexylamines/pharmacology ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Hedgehog Proteins/metabolism ; Kruppel-Like Factor 4 ; Kruppel-Like Transcription Factors/metabolism ; Mice ; Mice, Inbred ICR ; Mice, Transgenic ; Osteoblasts/cytology ; Osteoblasts/drug effects ; Pregnane X Receptor/genetics ; Pregnane X Receptor/metabolism ; Primary Cell Culture ; Signal Transduction ; Skull/cytology ; Skull/growth & development ; Skull/metabolism ; Smoothened Receptor/agonists ; Smoothened Receptor/genetics ; Smoothened Receptor/metabolism ; Thiophenes/pharmacology

Primary cilia are appendages observed in most types of cells, and serve as cellular antennae for sensing environmental signals. Evidence is accumulating that correct ciliogenesis and ciliary functions are indispensable for normal skeletal development by regulating signaling pathways important for bone development. However, whether ciliogenesis is regulated by bone-related factors in osteoblasts is largely unknown. Here we show that Kruppel-Like Factor 4 (KLF4), which is known to repress osteoblast differentiation, supports the formation and maintenance of cilia in cultured osteoblasts; however, the length of the cilia observed in KLF4-induced cells were significantly shorter compared to the control cells. Basal Hedgehog signaling was repressed by KLF4. Significantly, activating Hedgehog signaling using a Smoothened agonist significantly rescued osteoblast mineralization and osteoblastic gene expressions. Global gene expression analysis showed that KLF4 induced number of genes including the nuclear receptor, Pregnane X receptor (PXR), and PXR repressed calvarial osteoblast mineralization and repressed Gli1 expression similar as the effect observed by inducing KLF4. Our results implicate that KLF4 plays important roles for maintaining osteoblasts in an immature state by repressing basal activation of the Hedgehog signaling.
(Copyright © 2018 Elsevier Inc. All rights reserved.)

Keywords: Hedgehog; KLF4; Osteoblasts; Primary cilia; SXR/PXR/Nr1i2

0 (Cyclohexylamines)
0 (Hedgehog Proteins)
0 (Klf4 protein, mouse)
0 (Kruppel-Like Factor 4)
0 (Kruppel-Like Transcription Factors)
0 (Nr1i2 protein, mouse)
0 (Pregnane X Receptor)
0 (SAG compound)
0 (Shh protein, mouse)
0 (Smo protein, mouse)
0 (Smoothened Receptor)
0 (Thiophenes)

Date Created: 20180909 Date Completed: 20190918 Latest Revision: 20211204

20231215

10.1016/j.yexcr.2018.09.002

30193838