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Suppression of Sclerostin Alleviates Radiation‐Induced Bone Loss by Protecting Bone‐Forming Cells and Their Progenitors Through Distinct Mechanisms
Author(s) -
Chandra Abhishek,
Lin Tiao,
Young Tiffany,
Tong Wei,
Ma Xiaoyuan,
Tseng WeiJu,
Kramer Ina,
Kneissel Michaela,
Levine Michael A,
Zhang Yejia,
Cengel Keith,
Liu X. Sherry,
Qin Ling
Publication year - 2017
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.2996
Subject(s) - sclerostin , osteocyte , wnt signaling pathway , dna damage , osteoblast , microbiology and biotechnology , progenitor cell , cancer research , chemistry , bone marrow , stromal cell , dna repair , bone healing , mesenchymal stem cell , pathology , stem cell , biology , medicine , signal transduction , anatomy , in vitro , dna , biochemistry
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.