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Our previous in vitro study showed that activation of Wnt\/\u03b2-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\/\u03b2-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 \u03b3-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. \u00a9 2016 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2996","type":"journal-article","created":{"date-parts":[[2016,9,16]],"date-time":"2016-09-16T22:02:57Z","timestamp":1474063377000},"page":"360-372","source":"Crossref","is-referenced-by-count":117,"title":["Suppression of Sclerostin Alleviates Radiation-Induced Bone Loss by Protecting Bone-Forming Cells and Their Progenitors Through Distinct Mechanisms"],"prefix":"10.1093","volume":"32","author":[{"given":"Abhishek","family":"Chandra","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiao","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"},{"name":"Musculoskeletal Oncology CenterThe First Affiliated Hospital of Sun Yat-Sen UniversityGuangzhouChina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic SurgeryUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina"},{"name":"Department of Orthopaedic Surgery, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyuan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Ju","family":"Tseng","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ina","family":"Kramer","sequence":"additional","affiliation":[{"name":"Musculoskeletal Disease AreaNovartis Institutes for BioMedical ResearchBaselSwitzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Kneissel","sequence":"additional","affiliation":[{"name":"Musculoskeletal Disease AreaNovartis Institutes for BioMedical ResearchBaselSwitzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A","family":"Levine","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes and the Center for Bone HealthThe Children's Hospital of PhiladelphiaPhiladelphiaPAUSA"},{"name":"Department of PediatricsPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yejia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Philadelphia Veterans Affairs Medical Center and Department of Physical Medicine and RehabilitationPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"},{"name":"Department of Orthopaedic Surgery, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Cengel","sequence":"additional","affiliation":[{"name":"Department of Radiation OncologyPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X. 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