COX-2 Enzyme Stimulates Bone Repair

A study has revealed that absence of cyclo-oxygenase-2 (COX-2) diminishes the ability of stem cells to form bone cells, and that healing of fractures was significantly delayed in COX-2-deficient mice as compared with control mice. The findings were reported in the June 2002 issue of the Journal of Clinical Investigation.

Using mice that were deficient in COX-2 or COX-1, the investigators found that healing of stabilized tibia fractures was significantly delayed in the COX-2 mice compared with either the COX-1 mice or wild-type controls. The histology was characterized by a persistence of undifferentiated mesenchyme and a marked reduction in formation of new bone cells that resulted in a high incidence of fibrous nonunion in the COX-2 mice. Similarly, intramembranous bone formation on the calvaria was reduced 60% in COX-2 mice following in vivo injection of FGF-1 (fibroblast growth factor) or wild-type mice. The defect in formation of new bone cells was completely reversed by the addition of prostaglandin E2 (PGE2), the product of COX-2, to the cultures.

The defect in COX-2 cultures correlated with significantly reduced levels of cbfa1 and osterix, two genes necessary for bone formation. Addition of PGE2 reversed this defect, while BMP-2 enhanced cbfa1 and osterix in both COX-2 and wild-type cultures. These results provide a model of how COX-2 regulates the induction of cbfa1 and osterix to mediate normal skeletal repair.

"Our research for the first time pinpoints the unique mechanism of COX-2 in bone repair,” said Professor Regis O'Keefe, of the department of orthopedics at the University of Rochester Medical Center (New York, USA). "This study raises concerns regarding the use of COX-2 inhibitors in patients who suffer from bone fracture or who are undergoing other types of bone repair.”



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