title: Suppression of Sclerostin Alleviates Radiation-Induced Bone Loss by Protecting Bone-Forming Cells and Their Progenitors Through Distinct Mechanisms.
abstract: Focal radiotherapy is frequently associated with skeletal damage within the radiation field. Our previous in vitro study showed that activation of Wnt/β-catenin pathway can overcome radiation-induced DNA damage and apoptosis of osteoblastic cells. Neutralization of circulating sclerostin with a monoclonal antibody (Scl-Ab) is an innovative approach for treating osteoporosis by enhancing Wnt/β-catenin signaling in bone. Together with the fact that focal radiation increases sclerostin amount in bone, we sought to determine whether weekly treatment with Scl-Ab would prevent focal radiotherapy-induced osteoporosis in mice. Micro-CT and histomorphometric analyses demonstrated that Scl-Ab blocked trabecular bone structural deterioration after radiation by partially preserving osteoblast number and activity. Consistently, trabecular bone in sclerostin null mice was resistant to radiation via the same mechanism. Scl-Ab accelerated DNA repair in osteoblasts after radiation by reducing the number of γ-H2AX foci, a DNA double-strand break marker, and increasing the amount of Ku70, a DNA repair protein, thus protecting osteoblasts from radiation-induced apoptosis. In osteocytes, apart from using similar DNA repair mechanism to rescue osteocyte apoptosis, Scl-Ab restored the osteocyte canaliculi structure that was otherwise damaged by radiation. Using a lineage tracing approach that labels all mesenchymal lineage cells in the endosteal bone marrow, we demonstrated that radiation damage to mesenchymal progenitors mainly involves shifting their fate to adipocytes and arresting their proliferation ability but not inducing apoptosis, which are different mechanisms from radiation damage to mature bone forming cells. Scl-Ab treatment partially blocked the lineage shift but had no effect on the loss of proliferation potential. Taken together, our studies provide proof-of-principle evidence for a novel use of Scl-Ab as a therapeutic treatment for radiation-induced osteoporosis and establish molecular and cellular mechanisms that support such treatment. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Chandra
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Musculoskeletal Oncology Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Tiao
authors.initials: T
authors.lastname: Lin
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Young
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Orthopaedic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tong
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Wei-Ju
authors.initials: WJ
authors.lastname: Tseng
authors.affiliation: Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Ina
authors.initials: I
authors.lastname: Kramer
authors.affiliation: Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kneissel
authors.affiliation: Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Division of Endocrinology and Diabetes and the Center for Bone Health, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Levine
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Philadelphia Veterans Affairs Medical Center and Department of Physical Medicine and Rehabilitation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Yejia
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Cengel
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: X Sherry
authors.initials: XS
authors.lastname: Liu
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Qin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000473:pathology; D001862:Bone Resorption / Q000209:etiology* / Q000378:metabolism*; D000071556:Cancellous Bone / Q000473:pathology; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008648:Mesoderm / Q000473:pathology; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010011:Osteocytes / Q000187:drug effects / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D011832:Radiation Injuries / Q000150:complications* / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse
keywords: DNA REPAIR; MESENCHYMAL PROGENITORS; OSTEOBLASTS; RADIOTHERAPY; SCL-AB