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Tumor necrosis factor inhibits mesenchymal stem cell differentiation into osteoblasts via the ubiquitin E3 ligase

Lan Zhao1, Jian Huang, Hengwei Zhang

  • 1Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA.

Stem Cells (Dayton, Ohio)
|August 3, 2011
PubMed

Insights

Tumor necrosis factor (TNF) impairs bone formation by increasing Wwp1 expression, which degrades JunB in mesenchymal stem cells (MSCs). Inhibiting Wwp1 may treat inflammation-related osteoporosis by promoting osteoblast differentiation.

Area of Science:

  • Biomedical Science
  • Cell Biology
  • Rheumatology

Background:

  • Chronic inflammatory disorders, like rheumatoid arthritis, are linked to osteoporosis.
  • Tumor necrosis factor (TNF) contributes to bone loss by increasing resorption and decreasing formation.
  • Mesenchymal stem cells (MSCs) are crucial for bone formation, differentiating into osteoblasts.

Purpose of the Study:

  • To investigate if TNF inhibits osteoblast differentiation by affecting MSC commitment.
  • To identify molecular mechanisms by which TNF impacts MSC osteogenic potential.
  • To explore Wwp1 as a therapeutic target for inflammation-mediated osteoporosis.

Main Methods:

  • Isolated MSC-enriched CD45(-) cells from TNF transgenic (TNF-Tg) mice and wild-type controls.
  • Utilized flow cytometry (FACS) and cell differentiation assays to assess osteogenic potential.
  • Examined gene and protein expression, including ubiquitin ligases like Wwp1 and transcription factors like JunB.
  • Performed Wwp1 knockdown and utilized Wwp1 knockout mice for mechanistic studies.

Main Results:

  • MSCs from TNF-Tg mice showed significantly reduced osteogenic potential and decreased expression of osteoblast markers.
  • Wwp1 expression was significantly increased in MSCs from TNF-Tg mice.
  • Wwp1 knockdown rescued the impaired osteoblast differentiation in TNF-Tg MSCs.
  • Wwp1 was found to promote ubiquitination and degradation of the osteogenic transcription factor JunB.
  • TNF injection in wild-type mice decreased MSC osteoblast differentiation and increased JunB ubiquitination, effects blocked in Wwp1(-/-) mice.

Conclusions:

  • Chronic TNF exposure upregulates Wwp1 in MSCs, leading to JunB degradation and impaired osteoblast differentiation.
  • Wwp1 acts as a key mediator of TNF-induced inhibition of osteogenesis.
  • Targeting Wwp1 in MSCs presents a potential therapeutic strategy to combat inflammation-associated osteoporosis.

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