Impaired fracture healing in the absence of TNF-α signaling: The role of TNF-α in endochondral cartilage resorption

Louis C. Gerstenfeld, T. J. Cho, T. Kon, T. Aizawa, A. Tsay, J. Fitch, G. L. Barnes, D. T. Graves, T. A. Einhorn

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286 Citations (Scopus)

Abstract

TNF-α is a major inflammatory factor that is induced in response to injury, and it contributes to the normal regulatory processes of bone resorption. The role of TNF-α during fracture healing was examined in wild-type and TNF-α receptor (p55-/-/p75 -/-)-deficient mice. The results show that TNF-α plays an important regulatory role in postnatal endochondral bone formation. Introduction: TNF-α is a major inflammatory factor that is induced as part of the innate immune response to injury, and it contributes to the normal regulatory processes of bone resorption. Methods: The role of TNF-α was examined in a model of simple closed fracture repair in wild-type and TNF-α receptor (p55-/-/p75-/-)-deficient mice. Histomorphometric measurements of the cartilage and bone and apoptotic cell counts in hypertrophic cartilage were carried out at multiple time points over 28 days of fracture healing (n = 5 animals per time point). The expression of multiple mRNAs for various cellular functions including extracellular matrix formation, bone resorption, and apoptosis were assessed (triplicate polls of mRNAs). Results and Conclusions: In the absence of TNF-α signaling, chondrogenic differentiation was delayed by 2-4 days but subsequently proceeded at an elevated rate. Endochondral tissue resorption was delayed 2-3 weeks in the TNF-α receptor (p55-/-/p75-/-)-deficient mice compared with the wild-type animals. Functional studies of the mechanisms underlying the delay in endochondral resorption indicated that TNF-α mediated both chondrocyte apoptosis and the expression of proresorptive cytokines that control endochondral tissue remodeling by osteoclasts. While the TNF-α receptor ablated animals show no overt developmental alterations of their skeletons, the results illustrate the primary roles that TNF-α function contributes to in promoting postnatal fracture repair as well as suggest that processes of skeletal tissue development and postnatal repair are controlled in part by differing mechanisms. In summary, these results show that TNF-α participates at several functional levels, including the recruitment of mesenchymal stem, apoptosis of hypertrophic chondrocytes, and the recruitment of osteoclasts function during the postnatal endochondral repair of fracture healing.

Original languageEnglish
Pages (from-to)1584-1592
Number of pages9
JournalJournal of Bone and Mineral Research
Volume18
Issue number9
DOIs
Publication statusPublished - 2003 Sep 1

Keywords

  • Chondrocyte apoptosis
  • Fracture healing
  • Resorption
  • TNF-α

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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    Gerstenfeld, L. C., Cho, T. J., Kon, T., Aizawa, T., Tsay, A., Fitch, J., Barnes, G. L., Graves, D. T., & Einhorn, T. A. (2003). Impaired fracture healing in the absence of TNF-α signaling: The role of TNF-α in endochondral cartilage resorption. Journal of Bone and Mineral Research, 18(9), 1584-1592. https://doi.org/10.1359/jbmr.2003.18.9.1584