Blockade of TNFR1 signaling: A role of oscillatory fluid shear stress in osteoblasts

Haifang Wang, Suzanne R. Young, Rita Gerard-O'Riley, Julia M. Hum, Zhouqi Yang, Joseph Bidwell, Fredrick Pavalko

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Fluid shear stress protects cells from TNF-α-induced apoptosis. Oscillatory fluid shear stress (OFSS) is generally perceived as physiologically relevant biophysical signal for bone cells. Here we identify several cellular mechanisms responsible for mediating the protective effects of OFSS against TNF-α-induced apoptosis in vitro. We found that exposure of MC3T3-E1 osteoblast-like cells to as little as 5min of OFSS suppressed TNF-α-induced activation of caspase-3, cleavage of PARP and phosphorylation of histone. In contrast, H2O2-induced apoptosis was not inhibited by OFSS suggesting that OFSS might not be protecting cells from TNF-α-induced apoptosis via stimulation of global pro-survival signaling pathways. In support of this speculation, OFSS inhibition of TNF-α-induced apoptosis was unaffected by inhibitors of several pro-survival signaling pathways including pI3-kinase (LY294002), MAPK/ERK kinase (PD98059 or U0126), intracellular Ca2+ release (U73122), NO production (L-NAME), or protein synthesis (cycloheximide) that were applied to cells during exposure to OFSS and during TNF-α treatment. However, TNF-α-induced phosphorylation and degradation of IκBα was blocked by pre-exposure of cells to OFSS suggesting a more specific effect of OFSS on TNF-α signaling. We therefore focused on the mechanism of OFSS regulation of TNF-receptor 1 (TNFR1) signaling and found that OFSS (1) reduced the amount of receptor on the cell surface, (2) prevented the association of ubiquitinated RIP in TNFR1 complexes with TRADD and TRAF2, and (3) reduced TNF-α-induced IL-8 promoter activity in the nucleus. We conclude that the anti-apoptotic effect of OFSS is not mediated by activation of universal pro-survival signaling pathways. Rather, OFSS inhibits TNF-α-induced pro-apoptotic signaling which can be explained by the down-regulation of TNFR1 on the cell surface and blockade of TNFR1 downstream signaling by OFSS.

Original languageEnglish
Pages (from-to)1044-1051
Number of pages8
JournalJournal of Cellular Physiology
Volume226
Issue number4
DOIs
StatePublished - Apr 2011

Fingerprint

Tumor Necrosis Factor Receptors
Osteoblasts
Shear stress
Fluids
Apoptosis
TNF Receptor-Associated Factor 2
Phosphorylation
MAP Kinase Kinase Kinases
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
NG-Nitroarginine Methyl Ester
Cell Surface Receptors
Cycloheximide
Interleukin-8
Caspase 3
Histones
Down-Regulation
Chemical activation
Bone and Bones
Proteins

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Blockade of TNFR1 signaling : A role of oscillatory fluid shear stress in osteoblasts. / Wang, Haifang; Young, Suzanne R.; Gerard-O'Riley, Rita; Hum, Julia M.; Yang, Zhouqi; Bidwell, Joseph; Pavalko, Fredrick.

In: Journal of Cellular Physiology, Vol. 226, No. 4, 04.2011, p. 1044-1051.

Research output: Contribution to journalArticle

Wang, Haifang ; Young, Suzanne R. ; Gerard-O'Riley, Rita ; Hum, Julia M. ; Yang, Zhouqi ; Bidwell, Joseph ; Pavalko, Fredrick. / Blockade of TNFR1 signaling : A role of oscillatory fluid shear stress in osteoblasts. In: Journal of Cellular Physiology. 2011 ; Vol. 226, No. 4. pp. 1044-1051.
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