Association of microsomal prostaglandin E synthase 1 deficiency with impaired fracture healing, but not with bone loss or osteoarthritis, in mouse models of skeletal disorders

Abstract

Objective. Prostaglandin E synthase (PGES) functions as the terminal enzyme in the biosynthesis of prostaglandin E 2 (PGE 2 ) and is a potent regulator of bone and cartilage metabolism. Among the 3 isozymes of PGES, microsomal PGES-1 (mPGES-1) is known to play the most critical role in the production of PGE 2 in pathophysiologic events. This study investigated the roles of mPGES-1 under normal physiologic and pathophysiologic conditions in the skeletons of mPGES-1-deficient (mPGES-1 ؊/؊ ) mice. Methods. Skeletons of mPGES-1؊/؊ mice and their wild-type littermates were compared by radiologic and histologic analyses. Four models of skeletal disorders were created: bone loss induced by ovariectomy, bone loss induced by hind limb unloading, osteoarthritis (OA) induced by instability in the knee joint, and bone fracture by osteotomy at the tibial midshaft. Expression of the PGES enzymes was examined by immunohistochemistry and real-time reverse transcription-polymerase chain reaction. The cellular mechanism of fracture healing was examined in ex vivo cultures of costal cartilage chondrocytes.Results. Microsomal PGES-1 ؊/؊ mice had unaffected skeletal phenotypes under normal physiologic conditions. In the bone fracture model, fracture healing was impaired by the mPGES-1 deficiency, with half of the mice remaining in a non-bone union state even after 21 days; normal fracture healing was restored by adenoviral reintroduction of mPGES-1. The other skeletal disorders were not affected by the mPGES-1 deficiency. In vivo and ex vivo analyses revealed an impaired proliferation of chondrocytes in cartilage with the mPGES-1 deficiency, at an early stage of fracture healing.Conclusion. In these mouse models of skeletal disorders, mPGES-1 was indispensable for bone repair through chondrocyte proliferation, but was not essential for the skeleton under normal physiologic conditions, nor did it play a role in the pathophysiologic conditions of bone loss due to ovariectomy, bone loss due to unloading, or stress-induced OA.Prostaglandin E 2 (PGE 2 ) is produced in many types of tissue, including bone and cartilage, and has a broad range of biologic activities that are carried out via binding to 4 different G protein-coupled receptors, EP1, EP2, EP3, and EP4, which are linked to different intracellular signaling pathways (1,2). In the biosynthesis of PGE 2 , 3 enzymatic steps have been identified, involving phospholipase A 2 , cyclooxygenase (COX), and prostaglandin E synthase (PGES).PGES, the terminal enzyme that catalyzes the conversion of PGH 2 to PGE 2 , exists as 2 membraneassociated enzymes, microsomal PGES-1 (mPGES-1)

Inhibition of Matrix Metalloproteinase-3 and -13 Synthesis Induced by IL-1β in Chondrocytes from Mice Lacking Microsomal Prostaglandin E Synthase-1

“…Therefore, the overexpression of TIMP-3 observed in mPGES-1 null mice could represent a protection against cartilage degradation in arthritis. It may explain, at least in part, the persistance of cartilage degradation in surgically induced OA in mPGES-1 null mice (45).…”

Heme oxygenase-1 induction modulates microsomal prostaglandin E synthase-1 expression and prostaglandin E2 production in osteoarthritic chondrocytes

“…Although some studies have reported that mice lacking mPGES-1 do not show significant differences with respect to wild type animals in OA induced by surgical procedures [11], it is interesting to note that mPGES-1 defficiency results in milder arthritis and lower cartilage degradation [12].…”

Fracture healing and lipid mediators

“…Genetic ablation of mPGES-1 in mice has no apparent effects on normal skeletal development but causes a significant impairment in tibial fracture healing. 23 Tibial fractures in 5 of 10 mPGES-1-null mice failed to heal after 21 days, whereas 10 of 10 fractures healed in control mice. Levels of mPGES-1 mRNA peaked at 7 days after fracture in the mouse tibiae, which correlates with the peak period of callus cartilage formation.…”