title: PTH1-34 blocks radiation-induced osteoblast apoptosis by enhancing DNA repair through canonical Wnt pathway.
abstract: Focal radiotherapy for cancer patients has detrimental effects on bones within the radiation field and the primary clinical signs of bone damage include the loss of functional osteoblasts. We reported previously that daily injection of parathyroid hormone (PTH, 1-34) alleviates radiation-induced osteopenia in a preclinical radiotherapy model by improving osteoblast survival. To elucidate the molecular mechanisms, we irradiated osteoblastic UMR 106-01 cells and calvarial organ culture and demonstrated an anti-apoptosis effect of PTH1-34 on these cultures. Inhibitor assay indicated that PTH exerts its radioprotective action mainly through protein kinase A/β-catenin pathway. γ-H2AX foci staining and comet assay revealed that PTH efficiently promotes the repair of DNA double strand breaks (DSBs) in irradiated osteoblasts via activating the β-catenin pathway. Interestingly, Wnt3a alone also blocked cell death and accelerated DNA repair in primary osteoprogenitors, osteoblastic and osteocytic cells after radiation through the canonical signaling. Further investigations revealed that both Wnt3a and PTH increase the amount of Ku70, a core protein for initiating the assembly of DSB repair machinery, in osteoblasts after radiation. Moreover, down-regulation of Ku70 by siRNA abrogated the prosurvival effect of PTH and Wnt3a on irradiated osteoblasts. In summary, our results identify a novel role of PTH and canonical Wnt signaling in regulating DSB repair machinery and apoptosis in osteoblasts and shed light on using PTH1-34 or Wnt agonist as possible therapy for radiation-induced osteoporosis.
authors.affiliation: From the Department of Orthopaedic Surgery.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Chandra
authors.affiliation: From the Department of Orthopaedic Surgery, the Department of Orthopaedic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
authors.forename: Tiao
authors.initials: T
authors.lastname: Lin
authors.affiliation: From the Department of Orthopaedic Surgery.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhu
authors.affiliation: From the Department of Orthopaedic Surgery, the Department of Orthopaedic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 Hubei, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tong
authors.affiliation: the Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08903, and.
authors.forename: Yanying
authors.initials: Y
authors.lastname: Huo
authors.affiliation: From the Department of Orthopaedic Surgery.
authors.forename: Haoruo
authors.initials: H
authors.lastname: Jia
authors.affiliation: Departments of Physical Medicine & Rehabilitation and Orthopedic Surgery, and the Translational Musculoskeletal Research Center, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania 19104.
authors.forename: Yejia
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Department of Orthopaedic Surgery.
authors.forename: X Sherry
authors.initials: XS
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Keith
authors.initials: K
authors.lastname: Cengel
authors.affiliation: the Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08903, and.
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.affiliation: From the Department of Orthopaedic Surgery, qinling@mail.med.upenn.edu.
authors.forename: Ling
authors.initials: L
authors.lastname: Qin
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects* / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D000072200:Ku Autoantigen; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D010011:Osteocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D012886:Skull / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D046509:Tissue Culture Techniques; D060509:Wnt3A Protein / Q000378:metabolism / Q000494:pharmacology; D014965:X-Rays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D034961:Antigens, Nuclear; C495268:Ctnnb1 protein, rat; D004268:DNA-Binding Proteins; D010281:Parathyroid Hormone; D011837:Radiation-Protective Agents; D011994:Recombinant Proteins; D060509:Wnt3A Protein; D051176:beta Catenin; D017868:Cyclic AMP-Dependent Protein Kinases; C000606511:Xrcc6 protein, rat; D000072200:Ku Autoantigen
keywords: Apoptosis; DNA Repair; Ionizing Radiation; Osteoblast; Parathyroid Hormone; Wnt Pathway