Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone.
Glucocorticoid-induced bone disease is characterized by decreased bone formation and in situ death of isolated segments of bone (osteonecrosis) suggesting that glucocorticoid excess, the third most common cause of osteoporosis, may affect the birth or death rate of bone cells, thus reducing their numbers. To test this hypothesis, we administered prednisolone to 7-mo-old mice for 27 d and found decreased bone density, serum osteocalcin, and cancellous bone area along with trabecular narrowing. These changes were accompanied by diminished bone formation and turnover, as determined by histomorphometric analysis of tetracycline-labeled vertebrae, and impaired osteoblastogenesis and osteoclastogenesis, as determined by ex vivo bone marrow cell cultures. In addition, the mice exhibited a threefold increase in osteoblast apoptosis in vertebrae and showed apoptosis in 28% of the osteocytes in metaphyseal cortical bone. As in mice, an increase in osteoblast and osteocyte apoptosis was documented in patients with glucocorticoid-induced osteoporosis. Decreased production of osteoclasts explains the reduction in bone turnover, whereas decreased production and apoptosis of osteoblasts would account for the decline in bone formation and trabecular width. Furthermore, accumulation of apoptotic osteocytes may contribute to osteonecrosis. These findings provide evidence that glucocorticoid-induced bone disease arises from changes in the numbers of bone cells.
Division of Endocrinology/Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, and the McClellan Veterans Affairs Medical Center GRECC, Little Rock, Arkansas 72205, USA. rweinstein@medlan.uams.edu
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RS
Weinstein
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Jilka
A M
AM
Parfitt
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SC
Manolagas
D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015519:Bone Density / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D001862:Bone Resorption; D001842:Bone and Bones / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects*; D010011:Osteocytes / Q000187:drug effects*; D010024:Osteoporosis / Q000139:chemically induced / Q000473:pathology; D011239:Prednisolone / Q000008:administration & dosage*; D013131:Spine / Q000187:drug effects
D005938:Glucocorticoids; D011239:Prednisolone