Tumor necrosis factor alpha (TNF-α) coordinately regulates the expression of specific matrix metalloproteinases (MMPS) and angiogenic factors during fracture healing

W. Lehmann, C. M. Edgar, K. Wang, T. J. Cho, G. L. Barnes, S. Kakar, D. T. Graves, J. M. Rueger, L. C. Gerstenfeld, T. A. Einhorn

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113 Scopus citations

Abstract

Recent studies from our laboratory demonstrate that TNF-α signaling contributes to the regulation of chondrocyte apoptosis and a lack of TNF-α signaling leads to a persistence of cartilaginous callus and delayed resorption of mineralized cartilage. This study examines how delays in the endochondral repair process affect the expression of specific mediators of proteolytic cartilage turnover and vascularization. Simple closed fractures were produced in wild type and TNF-α receptor (p55-/-/p75-/-)- deficient mice. Using ribonuclease protection assay (RPA) and microarray analysis, the expression of multiple mRNAs for various angiogenic factors and the metalloproteinase gene family were measured in fracture calluses. The direct actions of TNFα on the expression of specific angiogenic factors and metalloproteinases (MMPs) was examined in both cultured callus cells and articular chondrocytes to compare the effects of TNF-α in growth cartilage versus articular cartilage. MMPs 2, 9, 13, and 14 were quantitatively the most prevalent metalloproteases and all showed peaks in expression during the chondrogenic period. In the absence of TNF-α signaling, the expression of all of these mRNAs was reduced. The angiopoietin families of vascular regulators and their receptors were expressed at much higher levels than the VEGFs and their receptors and while the angiopoietins showed diminished or delayed expression in the absence of TNF-α signaling, VEGF and its receptors remained unaltered. The expression of vascular endothelial growth inhibitor (VEGI or TNFSF15) showed a near absence in its expression in the TNF-α receptor-deficient mice. In vitro assessment of cultured fracture callus cells in comparison to primary articular chondrocytes showed that TNF-α treatment specifically induced the expression of MMP9, MMP14, VEGI, and Angiopoietin 2. These results suggest that TNF-α signaling in chondrocytes controls vascularization of cartilage through the regulation of angiopoietin and VEGI factors which play counterbalancing roles in the induction of growth arrest, or apoptosis in endothelial cells. Furthermore, TNF-α appears to regulate, in part, the expression of two key proteolytic enzymes, MMP 9 and MMP14 that are known to be crucial to the progression of vascularization and turnover of mineralized cartilage. Thus, TNF-α signaling in healing fractures appears to coordinate the expression of specific regulators of endothelial cell survival and metalloproteolytic enzymes and is essential in the transition and progression of the endochondral phase of fracture repair.

Original languageEnglish (US)
Pages (from-to)300-310
Number of pages11
JournalBone
Volume36
Issue number2
DOIs
StatePublished - Feb 2005

Keywords

  • Angiogenesis
  • Bone repair
  • Matrix proteins

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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    Lehmann, W., Edgar, C. M., Wang, K., Cho, T. J., Barnes, G. L., Kakar, S., Graves, D. T., Rueger, J. M., Gerstenfeld, L. C., & Einhorn, T. A. (2005). Tumor necrosis factor alpha (TNF-α) coordinately regulates the expression of specific matrix metalloproteinases (MMPS) and angiogenic factors during fracture healing. Bone, 36(2), 300-310. https://doi.org/10.1016/j.bone.2004.10.010