title: Role of endoplasmic reticulum stress in disuse osteoporosis.
abstract: Osteoporosis is a major skeletal disease with low bone mineral density, which leads to an increased risk of bone fracture. Salubrinal is a synthetic chemical that inhibits dephosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) in response to endoplasmic reticulum (ER) stress. To understand possible linkage of osteoporosis to ER stress, we employed an unloading mouse model and examined the effects of salubrinal in the pathogenesis of disuse osteoporosis. The results presented several lines of evidence that osteoclastogenesis in the development of osteoporosis was associated with ER stress, and salubrinal suppressed unloading-induced bone loss. Compared to the age-matched control, unloaded mice reduced the trabecular bone area/total area (B.Ar/T.Ar) as well as the number of osteoblasts, and they increased the osteoclasts number on the trabecular bone surface in a time-dependent way. Unloading-induced disuse osteoporosis significantly increased the expression of Bip, p-eIF2α and ATF4 in short-term within 6h of tail suspension, but time-dependent decreased in HU2d to HU14d. Furthermore, a significant correlation of ER stress with the differentiation of osteoblasts and osteoclasts was observed. Administration of salubrinal suppressed the unloading-induced decrease in bone mineral density, B.Ar/T.Ar and mature osteoclast formation. Salubrinal also increased the colony-forming unit-fibroblasts and colony-forming unit-osteoblasts. It reduced the formation of mature osteoclasts, suppressed their migration and adhesion, and increased the expression of Bip, p-eIF2α and ATF4. Electron microscopy showed that rough endoplasmic reticulum expansion and a decreased number of ribosomes on ER membrane were observed in osteoblast of unloading mice, and the abnormal ER expansion was significantly improved by salubrinal treatment. A TUNEL assay together with CCAAT/enhancer binding protein homologous protein (CHOP) expression indicated that ER stress-induced osteoblast apoptosis was rescued by salubrinal. Collectively, the results support the notion that ER stress plays a key role in the pathogenesis of disuse osteoporosis, and salubrinal attenuates unloading-induced bone loss by altering proliferation and differentiation of osteoblasts and osteoclasts via eIF2α signaling.
authors.affiliation: Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin 300457, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin 300457, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin 300457, China; Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Xinle
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin 300457, China; Department of Pharmacology, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin 300100, China.
authors.forename: Daquan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Zhaonan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Jialu
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Tan
authors.affiliation: Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Jiuguo
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Fanglin
authors.initials: F
authors.lastname: Gou
authors.affiliation: Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, IN 46202, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yokota
authors.affiliation: Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin 300457, China; Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300070, China; Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, IN 46202, USA. Electronic address: pizhang2008@163.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight; D001862:Bone Resorption / Q000188:drug therapy / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology / Q000627:therapeutic use; D003114:Colony-Forming Units Assay; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019417:Hindlimb Suspension; D008810:Mice, Inbred C57BL; D020966:Muscular Disorders, Atrophic / Q000150:complications* / Q000188:drug therapy / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D010006:Osteoblasts / Q000473:pathology / Q000648:ultrastructure; D010010:Osteoclasts / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D010024:Osteoporosis / Q000150:complications* / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D055114:X-Ray Microtomography
chemical_list: D002934:Cinnamates; D050778:NFATC Transcription Factors; C496827:salubrinal; D013890:Thiourea
keywords: Disuse; Endoplasmic reticulum stress; Eukaryotic translation initiation factor 2α; Hindlimb unloading; Osteoporosis; Salubrinal