Aging
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Research Article
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Gal Markel, Dana Wolf, Jacob Hanna, Roi Gazit, Debra Goldman-Wohl, Yuval Lavy, Simcha Yagel, Ofer Mandelboim
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Yoram G. Weiss, Alina Maloyan, John Tazelaar, Nichelle Raj, Clifford S. Deutschman
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Gillian S. Ashcroft, Stuart J. Mills
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Burkhard Becher, Brigit G. Durell, Randolph J. Noelle
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Wolfgang Dummer, Andreas G. Niethammer, Roberto Baccala, Brian R. Lawson, Norbert Wagner, Ralph A. Reisfeld, Argyrios N. Theofilopoulos
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William A. Chutkow, Jielin Pu, Matthew T. Wheeler, Tomoyuki Wada, Jonathan C. Makielski, Charles F. Burant, Elizabeth M. McNally
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Gregorio D. Chazenbalk, Pavel Pichurin, Chun-Rong Chen, Francesco Latrofa, Alan P. Johnstone, Sandra M. McLachlan, Basil Rapoport
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Research Article
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Hiroshi Yamamoto, Charlotte E. Lee, Jacob N. Marcus, Todd D. Williams, J. Michael Overton, Marisol E. Lopez, Anthony N. Hollenberg, Laurie Baggio, Clifford B. Saper, Daniel J. Drucker, Joel K. Elmquist
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Research Article
Authors
Khadija Rafiq, Amy Bergtold, Raphael Clynes
Abstract
Preclinical and clinical studies suggest a possible role for cyclooxygenases in bone repair and create concerns about the use of nonsteroidal antiinflammatory drugs in patients with skeletal injury. We utilized wild-type, COX-1–/–, and COX-2–/– mice to demonstrate that COX-2 plays an essential role in both endochondral and intramembranous bone formation during skeletal repair. The healing of stabilized tibia fractures was significantly delayed in COX-2–/– mice compared with COX-1–/– and wild-type controls. The histology was characterized by a persistence of undifferentiated mesenchyme and a marked reduction in osteoblastogenesis 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 compared with either COX-1–/– or wild-type mice. To elucidate the mechanism involved in reduced bone formation, osteoblastogenesis was studied in bone marrow stromal cell cultures obtained from COX-2–/– and wild-type mice. Bone nodule formation was reduced 50% in COX-2–/– mice. The defect in osteogenesis was completely rescued by addition of prostaglandin E2 (PGE2) to the cultures. In the presence of bone morphogenetic protein (BMP-2), bone nodule formation was enhanced to a similar level above that observed with PGE2 alone in both control and COX-2–/– cultures, indicating that BMPs complement COX-2 deficiency and are downstream of prostaglandins. Furthermore, we found that the defect in COX-2–/– cultures correlated with significantly reduced levels of cbfa1 and osterix, two genes necessary for bone formation. Addition of PGE2 rescued this defect, while BMP-2 enhanced cbfa1 and osterix in both COX-2–/– and wild-type cultures. Finally, the effects of these agents were additive, indicating that COX-2 is involved in maximal induction of osteogenesis. These results provide a model whereby COX-2 regulates the induction of cbfa1 and osterix to mediate normal skeletal repair.
Authors
Xinping Zhang, Edward M. Schwarz, Donald A. Young, J. Edward Puzas, Randy N. Rosier, Regis J. O’Keefe
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