Dataset Information

Importin-7 Promotes Tension-Induced Osteogenesis by Regulating RUNX2 Nuclear Translocation during Orthodontic Tooth Movement

ABSTRACT: Orthodontic tooth movement (OTM) is primarily driven by alveolar bone remodeling, wherein tension-induced osteogenesis plays a central role. Importin7 (IPO7) has been identified as a highly mechanoresponsive nuclear transport receptor (NTR). However, its role in regulating tension-induced osteogenesis during OTM and its underlying mechanism remains elusive. In the present study, cyclic tensile strain and a rat OTM model were used to investigate the role of IPO7. The results revealed that IPO7 was significantly expressed both in vitro and in vivo following exposure to mechanical stretch. Moreover, IPO7 knockdown inhibited tension-induced osteogenesis in BMSCs. Upon mechanical force stimulation, IPO7 translocated from the cytoplasm to the nucleus. Furthermore, immunoprecipitation (IP) coupled with mass spectrometry (MS) was performed and demonstrated that RUNX2 was one of the IPO7-interacting proteins related to osteogenesis. Although RUNX2 has been established to translocate to the nucleus to facilitate osteogenesis, whether it is IPO7 that regulate RUNX2 nuclear input during tension-induced osteogenesis remains to be determined. Then, the interaction between IPO7 and RUNX2 was further validated via co-immunoprecipitation (co-IP) and colocalization assays in BMSCs using immunofluorescence. Taken together, this study demonstrates that IPO7 promotes tension-induced osteogenesis by regulating the nucleoplasmic localization of RUNX2. Thus, targeting IPO7 may represent a prospective therapeutic strategy for enhancing alveolar bone remodeling and the efficacy of orthodontic treatment.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Stem Cell, Cell Culture

DISEASE(S): Disease Free

SUBMITTER: Leilei Zheng

LAB HEAD: Leilei Zheng

PROVIDER: PXD061760 | Pride | 2025-10-06

REPOSITORIES: Pride

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Publications

Importin-7 promotes tension-induced osteogenesis by regulating RUNX2 nuclear translocation during orthodontic tooth movement.

Yang Lan L Yang Guoyin G Yang Qing Q Zheng Leilei L

Scientific reports 20250926 1

Orthodontic tooth movement (OTM) is primarily driven by alveolar bone remodeling, wherein tension-induced osteogenesis plays a central role. Importin7 (IPO7) has been identified as a highly mechanoresponsive nuclear transport receptor (NTR). However, its role in regulating tension-induced osteogenesis during OTM and its underlying mechanism remains elusive. In the present study, cyclic tensile strain and a rat OTM model were used to investigate the role of IPO7. The results revealed that IPO7 wa ...[more]

PMID: 41006735

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Project description:Runx1 is highly expressed in osteoblasts, however, its function in osteogenesis is unclear. We generated mesenchymal progenitor-specific (Runx1f/fTwist2-Cre) and osteoblast-specific (Runx1f/fCol1α1-Cre) conditional knockout (Runx1 CKO) mice. The mutant CKO mice with normal skeletal development displayed a severe osteoporosis phenotype at postnatal and adult stages. Runx1 CKO resulted in decreased osteogenesis and increased adipogenesis. RNA-sequencing analysis, Western blot, and qPCR validation of Runx1 CKO samples showed that Runx1 regulates BMP signaling pathway and Wnt/β-catenin signaling pathway. ChIP assay revealed direct binding of Runx1 to the promoter regions of Bmp7, Alk3, and Atf4, and promoter mapping demonstrated that Runx1 upregulates their promoter activity through the binding regions. Bmp7 overexpression rescued Alk3, Runx2, and Atf4 expression in Runx1-deficient BMSCs. Runx2 expression was decreased while Runx1 was not changed in Alk3 deficient osteoblasts. Atf4 overexpression in Runx1-deficient BMSCs did not rescue expression of Runx1, Bmp7, and Alk3. Smad1/5/8 activity was vitally reduced in Runx1 CKO cells, indicating Runx1 positively regulates the Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 signaling pathway. Notably, Runx1 overexpression in Runx2-/- osteoblasts rescued expression of Atf4, OCN, and ALP to compensate Runx2 function. Runx1 CKO mice at various osteoblast differentiation stages reduced Wnt signaling and caused high expression of C/ebpα and Pparγ and largely increased adipogenesis. Co-culture of Runx1-deficient and wild-type cells demonstrated that Runx1 regulates osteoblast−adipocyte lineage commitment both cell-autonomously and non-autonomously. Notably, Runx1 overexpression rescued bone loss in OVX-induced osteoporosis. This study focused on the role of Runx1 in different cell populations with regards to BMP and Wnt signaling pathways and in the interacting network underlying bone homeostasis as well as adipogenesis, and has provided new insight and advancement of knowledge in skeletal development. Collectively, Runx1 maintains adult bone homeostasis from bone loss though up-regulating Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 and WNT/β-Catenin signaling pathways, and targeting Runx1 potentially leads to novel therapeutics for osteoporosis. Using unbiased genome-wide RNA-seq data from Runx1f/fCol1α1-Cre, Runx1ffTwist2-cre, Runx1f/f;Col2α1-Cre and their control osteoblasts, we examined Runx1-mediated transcriptional targets that could account for osteoblast differentiation defects and increased adipocytes.

Project description:Osteogenesis is a highly regulated developmental process and continues during the turnover and repair of mature bone. Runx2, the master regulator of osteoblastogenesis, directs a transcription program essential for bone formation through both genetic and epigenetic mechanisms. While individual Runx2 gene targets have been identified, further insights into the broad spectrum of Runx2 functions required for osteogenesis are needed. By performing genome-wide characterization of Runx2 binding at the three major stages of osteoblast differentiation: proliferation, matrix deposition and mineralization, we identified Runx2-dependent regulatory networks driving bone formation. Using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) over the course of these stages, we discovered close to 80,000 significantly enriched regions of Runx2 binding throughout the mouse genome. These binding events exhibited distinct patterns during osteogenesis, and were associated with proximal promoters as well as a large percentage of Runx2 occupancy in non-promoter regions: upstream, introns, exons, transcription termination site (TTS) regions, and intergenic regions. These peaks were partitioned into clusters that are associated with genes in complex biological processes that support bone formation. Using Affymetrix expression profiling of differentiating osteoblasts depleted of Runx2, we identified novel Runx2 targets including Ezh2, a critical epigenetic regulator; Crabp2, a retinoic acid signaling component; Adamts4 and Tnfrsf19, two remodelers of extracellular matrix. We demonstrated by luciferase assays that these novel biological targets are regulated by Runx2 occupancy at non-promoter regions. Our data establish that Runx2 interactions with chromatin across the genome reveal novel genes, pathways and transcriptional mechanisms that contribute to the regulation of osteoblastogenesis. MC3T3-E1 cells were treated with scramble or Runx2 shRNA, then harvested at proliferating stage (day 0) and differentiating stage (day 9). Total RNAs recovered from these cells were hybridization on Affymetrix microarrays. We sought to find new target genes or pathways regulated by Runx2 during osteoblast differentiation. When combined with genome-wide occupancy of Runx2, we expect to gain new insights on how Runx2 controls a transcriptional program essential for osteoblast differentiation.

			Action	DRS
	SERCH-F-IPO7.zip	Other
	SERCH-Igg.zip	Other
	SERCH-N-IPO7.zip	Other
	XA02057LI_F_IPO7.raw	Raw
	XA02057LI_Igg.raw	Raw