title: Clomipramine causes osteoporosis by promoting osteoclastogenesis via E3 ligase Itch, which is prevented by Zoledronic acid.
abstract: Patients taking antidepressants, including Clomipramine (CLP), have an increased risk of osteoporotic fracture. However, the effects of CLP on bone metabolism are unknown. Here, we demonstrate that WT mice treated with CLP for 2 weeks had significantly reduced trabecular bone volume and cortical bone thickness, associated with increased osteoclast (OC) numbers, but had no change in osteoblast numbers or bone formation rate. Bone marrow cells from CLP-treated mice had normal OC precursor frequency, but formed significantly more OCs when they were cultured with RANKL and M-CSF. CLP promoted OC formation and bone resorption and expression of OC-associated genes. CLP-induced bone loss was prevented by Zoledronic acid. At the molecular level, CLP inhibited the activity of the ubiquitin E3 ligase Itch. CLP did not promote OC formation from bone marrow cells of Itch-/- mice in vitro nor induce bone loss in Itch-/- mice. Our findings indicate that CLP causes bone loss by enhancing Itch-mediated osteoclastogenesis, which was prevented by Zoledronic acid. Thus, anti-resorptive therapy could be used to prevent bone loss in patients taking antidepressants, such as CLP.
authors.affiliation: Department of Immuno-oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.|Institute of Chinese Minority Traditional Medicine, MINZU University of China, Beijing 100081, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Hengwei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Chinese Minority Traditional Medicine, MINZU University of China, Beijing 100081, China.
authors.forename: Lingpeng
authors.initials: L
authors.lastname: Pei
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.|Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Boyce
authors.affiliation: Department of Immuno-oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.|Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Lianping
authors.initials: L
authors.lastname: Xing
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000473:pathology / Q000517:prevention & control; D002452:Cell Count; D002997:Clomipramine / Q000009:adverse effects*; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D010010:Osteoclasts / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects; D010024:Osteoporosis / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases; D002997:Clomipramine