title: Halofuginone prevents estrogen-deficient osteoporosis in mice.
abstract: Osteoporosis is characterized by enhanced activity of osteoclasts relative to that of osteoblasts. Thus, the principal means of treating the most common form of osteoporosis, namely that attending menopause, is inhibition of osteoclast formation or function. We have demonstrated that the inflammatory cytokine, IL-17, mediates estrogen-deficient osteoporosis, in mice, and that genetic blockade of its function prevents ovariectomy-induced bone loss. We herein report that the febrifugine derivative, halofuginone, a small molecule drug, reduces abundance of Th-17 cells in mice and prevents estrogen-deficient osteoporosis by diminishing bone resorption without impacting osteogenesis. In keeping with IL-17 mediating its osteoclastogenic effects by promoting RANK ligand expression by osteoblasts, halofuginone does not directly inhibit the bone resorptive cell. Thus, halofuginone, which is presently FDA-approved for treatment of scleroderma, is a candidate therapeutic for post-menopausal osteoporosis.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Deselm
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.forename: Steven L
authors.initials: SL
authors.lastname: Teitelbaum
mesh_terms: D000818:Animals; D001835:Body Weight; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004967:Estrogens / Q000172:deficiency* / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis; D010024:Osteoporosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010052:Ovariectomy / Q000009:adverse effects; D010880:Piperidines / Q000627:therapeutic use*; D052999:Quinazolinones / Q000627:therapeutic use*; D053245:RANK Ligand / Q000378:metabolism
chemical_list: D050071:Bone Density Conservation Agents; D004967:Estrogens; D020381:Interleukin-17; D010880:Piperidines; D052999:Quinazolinones; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; C010176:halofuginone