Strontium ranelate treatment of human primary osteoblasts promotes an osteocyte-like phenotype while eliciting an osteoprotegerin response

• Published in: Osteoporosis international 2009-04, Vol.20 (4), p.653-664
• Main Authors: Atkins, G. J, Welldon, K. J, Halbout, P, Findlay, D. M
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Biological and medical sciences; Bone Density Conservation Agents - pharmacology; Calcification, Physiologic - drug effects; Calcification, Physiologic - genetics; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Diseases of the osteoarticular system; DMP-1; Dose-Response Relationship, Drug; Drug therapy; Endocrinology; Female; Gene Expression Regulation - drug effects; Humans; Medical sciences; Medicine; Medicine & Public Health; Menopause; OPG; Organometallic Compounds - pharmacology; Original Article; Orthopedics; Osteoblast; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteocyte; Osteocytes - drug effects; Osteocytes - metabolism; Osteoporosis; Osteoporosis. Osteomalacia. Paget disease; Osteoprotegerin - biosynthesis; Phenotype; Rheumatology; Sclerostin; Strontium ranelate; Thiophenes - pharmacology; Womens health
• ISSN: 0937-941X; 1433-2965
• DOI: 10.1007/s00198-008-0728-6

Summary The effect of strontium ranelate (SR) on human osteoblast differentiation was tested. SR induced osteoblastic proliferation, in vitro mineralization, and increased the expression of osteocyte markers. SR also elicited an osteoprotegerin (OPG) secretory response. We conclude that SR promotes the osteoblast maturation and osteocyte differentiation while promoting an additional antiresorptive effect. Introduction SR is a new treatment for osteoporosis that reduces the risk of hip and vertebral fractures in postmenopausal women. This study sought to investigate the extent, to which SR modulates human osteoblast differentiation. Methods Adult human primary osteoblasts (NHBC) were exposed to SR under mineralizing conditions in long-term cultures. Osteoblast differentiation status was investigated by cell-surface phenotypic analysis. Expression of genes associated with osteoblast/osteocyte differentiation was examined using real-time RT-PCR. Secreted OPG was assayed by enzyme-linked immunosorbent assay. Results SR significantly increased osteoblast replication. SR time- and dose-dependently induced an osteocyte-like phenotype, as determined by cell surface alkaline phosphatase and STRO-1 expression. SR at 5 mM or greater dramatically increased in vitro mineralization. In parallel, mRNA levels of dentin matrix protein (DMP)-1 and sclerostin were higher under SR treatment, strongly suggestive of the presence of osteocytes. SR also increased the OPG/RANKL ratio throughout the culture period, consistent with an effect to inhibit osteoblast-induced osteoclastogenesis. Conclusions This study suggests that SR can promote osteoblast maturation and an osteocyte-like phenotype. Coupled with its effect on the OPG/RANKL system, these findings are consistent with in vivo effects in patients receiving SR for the treatment of osteoporosis.