Risedronate inhibits bone marrow mesenchymal stem cell adipogenesis and switches RANKL/OPG ratio to impair osteoclast differentiation

• Published in: The Journal of surgical research Vol. 180; no. 1; pp. e21 - e29
• Main Authors: Jin, Jian, Wang, Liang, Wang, Xiao-kai, Lai, Ping-lin, Huang, Min-jun, Jin, Da-di, Zhong, Zhao-ming, Chen, Jian-ting, Bai, Xiao-chun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2013
• Subjects: Adipogenesis; Adipogenesis - drug effects; Bone Density Conservation Agents - pharmacology; Bone Marrow Cells - cytology; Bone Marrow Cells - drug effects; Bone marrow fat; Cell Differentiation - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Etidronic Acid - analogs & derivatives; Etidronic Acid - pharmacology; Humans; Mechanistic Target of Rapamycin Complex 1; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - drug effects; Multiprotein Complexes - antagonists & inhibitors; Osteoclast; Osteoclasts - cytology; Osteoclasts - drug effects; Osteoprotegerin; Osteoprotegerin - analysis; RANK Ligand - analysis; Receptor activator of nuclear factor-κB ligand; Risedronate; Risedronate Sodium; Surgery; TOR Serine-Threonine Kinases - antagonists & inhibitors; Risedronate; Bone marrow fat; Osteoclast; Receptor activator of nuclear factor-κB ligand; Adipogenesis; Osteoprotegerin
• DOI: 10.1016/j.jss.2012.03.018
• ISSN: 0022-4804; 1095-8673

Osteoporosis is accompanied by an increase in bone marrow adipose tissue. Bone marrow adipogenesis has emerged as a therapeutic target for prevention of bone loss. Amino-bisphosphonates have been widely used for treatment of osteoporosis, but the mechanism through which amino-bisphosphonates inhibit osteoporosis remains unclear. The purpose of this study is to investigate the effects of bisphosphonates on bone marrow adipogenesis and the pro-osteoclastic factors produced by adipocytes in bone marrow microenvironment. Human mesenchymal stem cells were obtained and purified from six volunteer donors. Each sample of cells was treated by increasing concentrations of risedronate with or without adipogenic induction for 14 d, and then droplets of the differentiated adipocytes were analyzed. The level of receptor activator of nuclear factor-κB ligand and osteoprotegerin, as well as pro-osteoclastic inflammatory factors interleukin-1, interleukin-6, and tumor necrosis factor α produced by adipocytes were evaluated by Western blot and ELISA assay. Moreover, the effect of risedronate on the activity of mammalian target of rapamycin complex 1, a key Ser/Thr kinase for initiation of adipocyte differentiation, was investigated. Risedronate not only dose-dependently inhibited the bone marrow adipogenesis from human mesenchymal stem cells but also suppressed receptor activator of nuclear factor-κB ligand, not osteoprotegerin, expression in differentiated adipocytes, as well as pro-osteoclastic inflammatory factors. Furthermore, the activity of mammalian target of rapamycin complex 1 was suppressed by risedronate. Our findings that risedronate influences the crosstalk between bone marrow adipocyte–osteoclast represent a novel mechanism for the anti-osteoporotic effects of risedronate.