Reduced COX-2 expression in aged mice is associated with impaired fracture healing

Amish A. Naik, Chao Xie, Michael J. Zuscik, Paul Kingsley, Edward M. Schwarz, Hani Awad, Robert Guldberg, Hicham Drissi, J. Edward Puzas, Brendan Boyce, Xinping Zhang, Regis J. O'Keefe

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

Abstract

The cellular and molecular events responsible for reduced fracture healing with aging are unknown. Cyclooxygenase 2 (COX-2), the inducible regulator of prostaglandin E2 (PGE2) synthesis, is critical for normal bone repair. A femoral fracture repair model was used in mice at either 7-9 or 52-56 wk of age, and healing was evaluated by imaging, histology, and gene expression studies. Aging was associated with a decreased rate of chondrogenesis, decreased bone formation, reduced callus vascularization, delayed remodeling, and altered expression of genes involved in repair and remodeling. COX-2 expression in young mice peaked at 5 days, coinciding with the transition of mesenchymal progenitors to cartilage and the onset of expression of early cartilage markers. In situ hybridization and immunohistochemistry showed that COX-2 is expressed primarily in early cartilage precursors that co-express col-2. COX-2 expression was reduced by 75% and 65% in fractures from aged mice compared with young mice on days 5 and 7, respectively. Local administration of an EP4 agonist to the fracture repair site in aged mice enhanced the rate of chondrogenesis and bone formation to levels observed in young mice, suggesting that the expression of COX-2 during the early inflammatory phase of repair regulates critical subsequent events including chondrogenesis, bone formation, and remodeling. The findings suggest that COX-2/EP4 agonists may compensate for deficient molecular signals that result in the reduced fracture healing associated with aging.

Original languageEnglish
Pages (from-to)251-264
Number of pages14
JournalJournal of Bone and Mineral Research
Volume24
Issue number2
DOIs
StatePublished - Feb 2009

Keywords

  • Aging
  • Cyclooxygenases
  • Endochondral ossification
  • Fracture
  • Prostaglandin E2

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