Physiological role of prostaglandin H2 synthase-2 (COX-2) in bone metabolism

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Prostaglandin E2 produced by prostaglandin H2 synthase (COX) has been to be forcused on the bone forming factor as well as bone resorbing factor. COXs have two isozymes, COX-1 and COX-2. In this study, we investigated that the physiological roles of COX-1 and COX-2 in bone metabolism. When IL-1 added to the bone marrow culture, in which stem cells can be differentiated to osteoclasts, the expression of COX-2 mRNA and protein in osteoblasts were stimulated by IL-1 and the PGE2 produced by COX-2 supported the osteoclast formation.In contrast, the osteoclast formation induced by IL-6, PTH and 1,25- (OH) 2 vitamin D3 was thought to be independent to prostaglandin synthesis, but COX inhibitor also inhibited the osteoclast formation induced by them. In this study, we also tried to be clear the mechanisms for the involvement of prostaglandins in these systems. In order to examine this, we applied the assay system for measuring COX activity in individual intact cell. The cells cultured with PTH expressed COX activity whereas the cells cultured without PTH did not express COX activity. The PG synthetic activity was observed in tartrate-resistant acid phosphatase positive mononucleated cells as well as osteoblastic cells. Moreover, the PG activity in the cells during the late phase of the culture was significantly inhibited by NS-398, a specific inhibitor of COX-2. These data indicate that the COX-2 expression in preosteoclasts is necessary for the differentiation to osteoclasts. Next, we examined the role of COX-2 in bone formation. The PGE2 produced by COX-2 stimulated VFGF production in osteoblasts, and the produced VEGF stimulated angiogenesis in the newly synthesized bone and may have the role of maintenance of bone.In conclusion, it is clearly demonstrated in this study that COX-2 is an important enzyme for bone metabolism.