The effects of COX-1 and COX-2 inhibitors on prostaglandin synthesis and the formation of heterotopic bone in a rat model.
BACKGROUND
Traumatic heterotopic ossification (HO) is a common clinical condition associated with various orthopedic procedures that involve injury to soft tissues near bone. In this study, we tested the hypothesis that the prophylactic effects of NSAID's in the treatment of HO are mediated via inhibition of the COX-2 enzyme. Here we describe a rat model that simulates HO in the human that was used to test the above hypothesis.


METHODS
Heterotopic ossification was surgically induced in the quadriceps by injury to the muscle and femoral periosteum and transplantation of donor bone marrow cells containing osteoprogenitors into the site of injury. HO was imaged and quantified by micro-CT scanning of femurs removed from sacrificed animals at 6 weeks post-injury, three-dimensional computer reconstructions of the scanned bones and computer-assisted morphometric analysis. Prostaglandin E(2) (PGE(2)) synthesis was quantified using an enzyme immunoassay system. The effects of a nonselective COX inhibitor or specific inhibitors of COX-1 or COX-2 following oral administration on the content of ectopic bone and PGE(2) were also measured.


RESULTS
Micro-CT and histological analyses demonstrated that all of the femurs in operated limbs developed HO in the vastus lateralis muscle belly of the quadriceps close to the anterior femur. Only the COX-1,2 nonselective and COX-2 inhibitors significantly decreased HO formation (by about one-third in each case; P < 0.05). PGE(2) synthesis at the site of injury was increased 50- and 100-fold (to 25 ng/g tissue) within 1 and 7 days, respectively, post-injury with the levels declining to near baseline within 2 weeks of surgery. Both the COX-1,2 nonselective and COX-2 inhibitors significantly decreased PGE(2) levels to 25% of control HO levels within 24 h of the first administration, even at low dosages. The COX-1 inhibitor only produced the same effect after 1 week of administration.


CONCLUSIONS
These findings suggest that although inhibitors of COX-2 or COX-1 reduced PGE(2) synthesis, only the COX-2 enzyme plays a role in the mechanism of traumatic HO.
Rapuano
Bruce E
BE
Research Division, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA. Rapuanob@hss.edu
Boursiquot
Roosevelt
R
Tomin
Emre
E
Macdonald
Daniel E
DE
Maddula
Surekha
S
Raghavan
Deepak
D
Lane
Joseph M
JM
Helfet
David L
DL
D000818:Animals; D000068579:Celecoxib; D051545:Cyclooxygenase 1 / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D008565:Membrane Proteins / Q000502:physiology; D009999:Ossification, Heterotopic / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000201:enzymology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013449:Sulfonamides / Q000494:pharmacology; D014057:Tomography, X-Ray Computed
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; D000068579:Celecoxib