Chandra, Abhishek, Lin, Tiao, Young, Tiffany, Tong, Wei, Ma, Xiaoyuan, Tseng, Wei-Ju, Kramer, Ina, Kneissel, Michaela, Levine, Michael A., Zhang, Yejia, Cengel, Keith, Liu, X. Sherry and Qin, Ling (2016) Suppression of Sclerostin Alleviates Radiation-Induced Bone Loss by Protecting Bone-Forming Cells and Their Progenitors Through Distinct Mechanisms. Journal of Bone & Mineral Research, 16. ISSN 1523-4681

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.

Item Type:	Article
Additional Information:	Unmapped bibliographic data: LA - English [Field not mapped to EPrints] ST - Suppression of Sclerostin Alleviates Radiation-Induced Bone Loss by Protecting Bone Forming Cells and Their Progenitors through Distinct Mechanisms [Field not mapped to EPrints] AU - Chandra, A. [Field not mapped to EPrints] AU - Lin, T. [Field not mapped to EPrints] AU - Young, T. [Field not mapped to EPrints] AU - Tong, W. [Field not mapped to EPrints] AU - Ma, X. [Field not mapped to EPrints] AU - Tseng, W. J. [Field not mapped to EPrints] AU - Kramer, I. [Field not mapped to EPrints] AU - Kneissel, M. [Field not mapped to EPrints] AU - Levine, M. A. [Field not mapped to EPrints] AU - Zhang, Y. [Field not mapped to EPrints] AU - Cengel, K. [Field not mapped to EPrints] AU - Liu, X. S. [Field not mapped to EPrints] AU - Qin, L. [Field not mapped to EPrints] J2 - J Bone Miner Res [Field not mapped to EPrints] AD - Chandra,Abhishek. Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104. [Field not mapped to EPrints] M3 - Journal article [Field not mapped to EPrints] DB - MEDLINE [Field not mapped to EPrints] DP - Ovid Technologies [Field not mapped to EPrints] AN - 27635523 [Field not mapped to EPrints]
Date Deposited:	24 Mar 2017 00:45
Last Modified:	24 Mar 2017 00:45
URI:	https://oak.novartis.com/id/eprint/29498