Radiotherapy is often used to eliminate tumor cells but can have untoward effects on neighboring normal tissues including bone, causing acute and chronic problems such as osteoradionecrosis, osteoporosis and fractures. In patients receiving radiotherapy in the pelvic region, the increased fracture incidence can be clinically significant, and pelvic fractures are a substantial cause of morbidity and mortality in the elderly. To date, there is no clinically proven treatment for this devastating disease. Bone health and skeletal homeostasis require constant bone turnover consisting of balanced bone formation and resorption. Using a newly available Small Animal Radiation Research Platform (SARRP), we recently established a rodent focal radiation model that reproduces many aspects of radiotherapy-induced damage on bone. Detailed analyses of this model demonstrated that radiation causes local trabecular bone loss by drastically and persistently reducing the number of osteoblast lineage cells, including osteoblasts and their mesenchymal progenitors. We initially found that daily injections of parathyroid hormone (PTH) largely prevented such bone loss and structural deterioration in irradiated bone and that the major mechanism appears to be the protection of osteoblasts from radiation- induced apoptosis via stimulating the PKA/-catenin pathway. Radiation exposure directly or indirectly generates a large amount of DNA lesions in cells, among which DNA double strand break (DSB) is the most deleterious one that causes cell death. Mechanistic studies showed that activating the canonical Wnt/-catenin signaling is capable of blocking radiation-induced apoptosis in osteoblast lineage cells by enhancing the repair of DSBs through a non-homologous end-joining pathway. Sclerostin is an osteocyte-secreted Wnt antagonist whose loss-of-function mutations lead to a high bone mass phenotype. Administration of antibody against sclerostin (Scl-Ab) elicited the same robust radioprotective actions on trabecular bone as PTH. Most strikingly, the damaging effects of radiation were completely abrogated in sclerostin knockout mice. We hypothesize that prolonged impairment of osteoblasts and their progenitors, which results in diminished bone formation, is a major cause of post-radiation bone deterioration and that anabolic Scl-Ab treatment is an effective therapy for radiation damage on bone by protecting bone-forming cells from apoptosis.
Our aims are to: 1) define the mechanism for radiation damage on bone, osteoblasts, and mesenchymal progenitors caused by clinically relevant focal radiotherapy; 2) characterize the rescue effects of Scl-Ab on radiation-induced damage on bone; 3) uncover the mechanism by which Scl-Ab preserves osteoblasts and their progenitors. This project will 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. Our long-term goal is to benefit millions of cancer patients by developing a therapy that allows the use of maximal radiotherapy doses on tumors while at the same time prevents the potentially severe bone-associated side effects.
Radiotherapy is a common cancer treatment but it has clinically significant side effects on the skeleton within the radiation field, leading to osteoporsis and fractures. This proposal will use a newly available irradiator for small animals to understand the mechanism of focal radiation damage on bone and investigate a novel use of anti-sclerostin antibody as a therapeutic treatment for radiation-induced osteoporosis. Findings gathered from these studies can be translated into a treatment regimen that will reduce the fracture risk in cancer patients who receive radiotherapy.
|Tian, Zuozhen; Ma, Xiaoyuan; Yasen, Miersalijiang et al. (2018) Intervertebral Disc Degeneration in a Percutaneous Mouse Tail Injury Model. Am J Phys Med Rehabil 97:170-177|
|Chandra, Abhishek; Wang, Luqiang; Young, Tiffany et al. (2018) Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis. FASEB J 32:52-62|
|Jia, Haoruo; Ma, Xiaoyuan; Wei, Yulong et al. (2018) Loading-Induced Reduction in Sclerostin as a Mechanism of Subchondral Bone Plate Sclerosis in Mouse Knee Joints During Late-Stage Osteoarthritis. Arthritis Rheumatol 70:230-241|
|Chandra, Abhishek; Lin, Tiao; Young, Tiffany et al. (2017) Suppression of Sclerostin Alleviates Radiation-Induced Bone Loss by Protecting Bone-Forming Cells and Their Progenitors Through Distinct Mechanisms. J Bone Miner Res 32:360-372|
|Tong, Wei; Lu, Zhouyu; Qin, Ling et al. (2017) Cell therapy for the degenerating intervertebral disc. Transl Res 181:49-58|
|Altman-Singles, Allison R; Jeong, Yonghoon; Tseng, Wei-Ju et al. (2017) Intermittent Parathyroid Hormone After Prolonged Alendronate Treatment Induces Substantial New Bone Formation and Increases Bone Tissue Heterogeneity in Ovariectomized Rats. J Bone Miner Res 32:1703-1715|
|Jia, Haoruo; Ma, Xiaoyuan; Tong, Wei et al. (2016) EGFR signaling is critical for maintaining the superficial layer of articular cartilage and preventing osteoarthritis initiation. Proc Natl Acad Sci U S A 113:14360-14365|
|Lin, Tiao; Tong, Wei; Chandra, Abhishek et al. (2015) A comprehensive study of long-term skeletal changes after spinal cord injury in adult rats. Bone Res 3:15028|
|Altman, Allison R; Tseng, Wei-Ju; de Bakker, Chantal M J et al. (2015) Quantification of skeletal growth, modeling, and remodeling by in vivo micro computed tomography. Bone 81:370-379|