Open AccessCannabinoid receptor 1 mediates glucocorticoid‐induced bone loss in rats by perturbing bone mineral acquisition and marrow adipogenesis
Author(s) -
Ko JihYang,
Wu ReWen,
Kuo ShuJui,
Chen MingWen,
Yeh DaWei,
Ke HueiChing,
Wu ShinLong,
Wang FengSheng
Publication year - 2012
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.33457
Subject(s) - endocrinology , medicine , osteoblast , glucocorticoid , adipogenesis , bone marrow , glucocorticoid receptor , am251 , bone mineral , adipose tissue , chemistry , biology , cannabinoid receptor , receptor , osteoporosis , agonist , biochemistry , in vitro
Objective Prolonged glucocorticoid treatment increases the risk of osteopenic disorders. Bone loss and marrow fat accumulation are prominent features of glucocorticoid‐induced skeletal destruction. Cannabinoid receptor 1 (CB 1 ) has been found to regulate energy expenditure and adipose tissue lipogenesis. We undertook this study to investigate whether CB 1 signaling regulates glucocorticoid‐induced bone loss. Methods Rats were administered glucocorticoid, CB 1 antisense oligonucleotide, CB 1 sense oligonucleotide, or the CB 1 antagonist AM251. Bone mineral density, microstructure, biomechanical strength, and signaling transduction were assessed by dual x‐ray absorptiometry, micro–computed tomography, material testing, and immunoblotting, respectively. Primary bone marrow stromal cells were isolated for assessment of ex vivo osteoblast and adipocyte differentiation. Results Glucocorticoid administration accelerated bone deterioration and fatty marrow formation in association with up‐regulation of CB 1 expression. Genetic and pharmacologic blockade of CB 1 by CB 1 antisense oligonucleotide and AM251 attenuated the deleterious effects of glucocorticoid treatment on bone mineral density, trabecular microarchitecture, and mechanical properties. CB 1 antagonism improved osteoblast survival, osteoblast surface, and bone mineral acquisition, but abrogated marrow adiposity. Knockdown of CB 1 restored osteogenic differentiation capacity and attenuated the promoting effects of glucocorticoid on adipogenic differentiation in primary bone marrow mesenchymal cells. CB 1 signaling modulated ERK, JNK, and Akt activation as well as runt‐related transcription factor 2 and peroxisome proliferator–activated receptor γ2 signaling. Adiponectin signaling was activated by CB 1 regulation of bone formation and fatty marrow. Conclusion CB 1 mediates glucocorticoid‐induced suppression of bone formation and marrow fat homeostasis. CB 1 antagonism reduces adipogenic and apoptotic reactions in bone microenvironments, thereby abrogating the deleterious effects of glucocorticoid treatment on bone integrity. Modulation of CB 1 signaling has therapeutic potential for preventing glucocorticoid‐induced osteopenic disorders.