Cannabinoid receptor 1 mediates glucocorticoid-induced bone loss in rats by perturbing bone mineral acquisition and marrow adipogenesis

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2012-04, Vol.64 (4), p.1204-1214
• Main Authors: Ko, Jih-Yang, Wu, Re-Wen, Kuo, Shu-Jui, Chen, Ming-Wen, Yeh, Da-Wei, Ke, Huei-Ching, Wu, Shin-Long, Wang, Feng-Sheng
• Format: Article
• Language: English
• Subjects: Adipogenesis - drug effects; Adipogenesis - physiology; Animals; Biological and medical sciences; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone density; Bone Density - drug effects; Bone Diseases, Metabolic - chemically induced; Bone Diseases, Metabolic - metabolism; Bone marrow; Calcification, Physiologic - drug effects; Diseases of the osteoarticular system; Glucocorticoids - pharmacology; Medical sciences; Older people; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteoporosis. Osteomalacia. Paget disease; Rats; Receptor, Cannabinoid, CB1 - metabolism
• ISSN: 0004-3591; 2326-5191; 1529-0131; 2326-5205
• DOI: 10.1002/art.33457

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 (CB1) has been found to regulate energy expenditure and adipose tissue lipogenesis. We undertook this study to investigate whether CB1 signaling regulates glucocorticoid‐induced bone loss. Methods Rats were administered glucocorticoid, CB1 antisense oligonucleotide, CB1 sense oligonucleotide, or the CB1 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 CB1 expression. Genetic and pharmacologic blockade of CB1 by CB1 antisense oligonucleotide and AM251 attenuated the deleterious effects of glucocorticoid treatment on bone mineral density, trabecular microarchitecture, and mechanical properties. CB1 antagonism improved osteoblast survival, osteoblast surface, and bone mineral acquisition, but abrogated marrow adiposity. Knockdown of CB1 restored osteogenic differentiation capacity and attenuated the promoting effects of glucocorticoid on adipogenic differentiation in primary bone marrow mesenchymal cells. CB1 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 CB1 regulation of bone formation and fatty marrow. Conclusion CB1 mediates glucocorticoid‐induced suppression of bone formation and marrow fat homeostasis. CB1 antagonism reduces adipogenic and apoptotic reactions in bone microenvironments, thereby abrogating the deleterious effects of glucocorticoid treatment on bone integrity. Modulation of CB1 signaling has therapeutic potential for preventing glucocorticoid‐induced osteopenic disorders.