OLMALINC/OCT4/BMP2 axis enhances osteogenic-like phenotype of renal interstitial fibroblasts to participate in Randall's plaque formation

Mol Med. 2022 Dec 29;28(1):162. doi: 10.1186/s10020-022-00576-4.

Abstract

Background: Randall's plaques (RP) are identified as anchored sites for kidney calcium oxalate stones, but the mechanism remains unclear. Given the importance of osteogenic-like cells in RP formation and OCT4 in reprogramming differentiated cells to osteoblasts, the current study explored the potential role of OCT4 in RP formation.

Methods: OCT4 and biomineralization were evaluated in RP, and immunofluorescence co-staining was performed to identify these cells with alteration of OCT4 and osteogenic markers. Based on the analysis of tissue, we further investigated the mechanism of OCT4 in regulating osteogenic-like differentiation of primary human renal interstitial fibroblasts (hRIFs) in vitro and vivo.

Results: We identified the upregulated OCT4 in RP, with a positive correlation to osteogenic markers. Interestingly, fibroblast marker Vimentin was partially co-localized with upregulated OCT4 and osteogenic markers in RP. Further investigations revealed that OCT4 significantly enhanced the osteogenic-like phenotype of hRIFs in vitro and in vivo. Mechanically, OCT4 directly bound to BMP2 promoter and facilitated its CpG island demethylation to transcriptionally promote BMP2 expression. Furthermore, combination of RIP and RNA profiling uncovered that lncRNA OLMALINC physically interacted with OCT4 to promote its stabilization via disrupting the ubiquitination. Additionally, OLMALINC was upregulated in fibroblasts in RP visualized by FISH, and a positive correlation was revealed between OLMALINC and OCT4 in RP.

Conclusions: The upregulation of OCT4 in hRIFs was a pathological feature of RP formation, and OLMALINC/OCT4/BMP2 axis facilitated hRIFs to acquire osteogenic-like phenotype under osteogenic conditions, through which the pathway might participate in RP formation. Our findings opened up a new avenue to better understand RP formation in which osteogenic-like process was partially triggered by lncRNAs and pluripotency maintenance related genes.

Keywords: BMP2; OCT4; OLMALINC; Osteogenic-like differentiation; Randall’s plaques; Renal interstitial fibroblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Protein 2* / genetics
  • Calcium Oxalate / metabolism
  • Fibroblasts / metabolism
  • Humans
  • Kidney / metabolism
  • Kidney Calculi* / metabolism
  • Kidney Medulla / pathology
  • Octamer Transcription Factor-3* / genetics
  • Phenotype
  • RNA, Long Noncoding* / genetics

Substances

  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • Calcium Oxalate
  • RNA, Long Noncoding
  • POU5F1 protein, human
  • Octamer Transcription Factor-3