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Do Cyclooxygenase-2 Knockout Mice Have Primary Hyperparathyroidism?

Departments of Medicine (M.X., S.C., L.R., C.P.) and Orthopedics (F.L., D.A., G.G., B.K.-J.), University of Connecticut Health Center, Farmington, Connecticut 06030; and Department of Medicine, McGill University Health Center and McGill University (D.G.), Montréal, Canada 3A 1A1

Address all correspondence and requests for reprints to: Dr. Carol Pilbeam, Room AM047, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030. E-mail: pilbeam{at}nso.uchc.edu.

The absence of cyclooxygenase-2 (COX-2) activity in vitro reduces differentiation of both bone-forming and bone-resorbing cells. To examine the balance of COX-2 effects on bone in vivo, we studied COX-2 knockout (KO) and wild-type (WT) mice. After weaning, KO mice died 4 times faster than WT mice, consistent with reports of progressive renal failure in KO mice. Among KO mice killed at 4 months of age, some had renal failure with marked secondary hyperparathyroidism, but others appeared healthy. On the assumption that renal failure was not inevitable in COX-2 KO mice and that phenotypic differences might increase with age, we studied KO mice surviving to 10 months of age with serum creatinine levels similar to those of WT mice. In 10-month-old male KO mice, serum calcium and PTH, but not phosphorus, levels were increased compared with those in WT mice. 1,25-Dihydroxyvitamin D₃ levels were markedly elevated in KO mice. Skeletal analysis showed small nonsignificant decreases in cortical bone density by BMD and either an increase (distal femur, by microcomputed tomography) or no difference (distal femur, by static histomorphometry) in trabecular bone density in KO mice. There was a trend toward increased percent osteoblastic and osteoclastic surfaces, and on dynamic histomorphometry, the rates of trabecular bone formation and mineral apposition were increased in KO mice relative to WT mice. Similar trends were observed for most parameters in 10-month-old female COX-2 KO mice. However, rates of trabecular bone formation and mineral apposition were increased in 10-month-old WT females compared with males and did not increase further in female KO mice. These data suggest that COX-2 KO mice with intact renal function have primary hyperparathyroidism, and that effects of increased PTH and 1,25-dihydroxyvitamin D₃ to increase bone turnover may compensate for the absence of COX-2.

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