Influence of radiation exposure pattern on the bone injury and osteoclastogenesis in a rat model

Zhai,Jianglong; He,Feilong; Wang,Jianping; Chen,Junxiang; Tong,Ling; Zhu,Guoying

doi:10.3892/ijmm.2019.4369

Influence of radiation exposure pattern on the bone injury and osteoclastogenesis in a rat model

Authors:
- Jianglong Zhai
- Feilong He
- Jianping Wang
- Junxiang Chen
- Ling Tong
- Guoying Zhu
View Affiliations

Affiliations: Department of Radiation Protection, Institute of Radiation Medicine, Fudan University, Shanghai 200032, P.R. China
Published online on: October 11, 2019 https://doi.org/10.3892/ijmm.2019.4369
Pages: 2265-2275
Copyright: © Zhai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Radiotherapy, one of the clinical treatments of cancer, is accompanied by a high risk of damage to healthy tissues, such as bone loss and increased risk of fractures. The aim of the present study was to establish a rat model of local and systemic bone injury by focal irradiation, in order to study the etiological mechanism and intervention. The proximal metaphyseal region of the left hindlimb of male Sprague‑Dawley rats were exposed to a single 2 Gy or three 8 Gy doses delivered on days 1, 3 and 5 using a small animal irradiator, the changes in bone volume and microarchitecture were evaluated, and the mineral apposition rate (MAR) was assessed. Furthermore, bone marrow‑derived macrophages (BMMs) were isolated and induced to osteoclasts. It has been demonstrated that a single dose of 2 Gy may result in a significant loss of lumbar bone density at 3 days post‑irradiation, however this is restored at 30 days post‑irradiation. In the 3x8 Gy irradiation rat model, there was a rapid decrease in the aBMD of lumbar spine at 3 days and at 7 days post‑irradiation, and the aBMD decline persisted even at 60 days post‑irradiation. In addition, microCT analysis revealed a persistent decline in bone volume and damage in microarchitecture in the 3x8 Gy irradiation model, accompanied by a decrease in MAR, index of the decline in bone‑forming ability. In the cellular mechanism, a single 2 Gy local irradiation mainly manifested as an enhancement of the BMMs osteoclastogenesis potential, which was different from the osteoclastogenesis inhibition after high‑dose focal irradiation (3x8 Gy). In summary, the irradiation with simulated clinical focal fractionated radiotherapy exerts short‑ and long‑term systemic injury on bone tissue, characterized by different osteoclastogenesis potential between the high dose mode and a single 2 Gy focal irradiation. Physicians must consider the irreversibility of bone damage in clinical radiotherapy.

View Figures

View References

1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	D'Oronzo S, Stucci S, Tucci M and Silvestris F: Cancer treatment-induced bone loss (CTIBL): Pathogenesis and clinical implications. Cancer Treat Rev. 41:798–808. 2015. View Article : Google Scholar : PubMed/NCBI
3	Fornetti J, Welm AL and Stewart SA: Understanding the bone in cancer metastasis. J Bone Miner Res. 33:2099–2113. 2018. View Article : Google Scholar : PubMed/NCBI
4	Baxter NN, Habermann EB, Tepper JE, Durham SB and Virnig BA: Risk of pelvic fractures in older women following pelvic irradiation. JAMA. 294:2587–2593. 2005. View Article : Google Scholar : PubMed/NCBI
5	Elliott SP, Jarosek SL, Alanee SR, Konety BR, Dusenbery KE and Virnig BA: Three-dimensional external beam radiotherapy for prostate cancer increases the risk of hip fracture. Cancer. 117:4557–4565. 2011. View Article : Google Scholar : PubMed/NCBI
6	Body JJ, Terpos E, Tombal B, Hadji P, Arif A, Young A, Aapro M and Coleman R: Bone health in the elderly cancer patient: A SIOG position paper. Cancer Treat Rev. 51:46–53. 2016. View Article : Google Scholar : PubMed/NCBI
7	Handforth C, D'Oronzo S, Coleman R and Brown J: Cancer treatment and bone health. Calcif Tissue Int. 102:251–264. 2018. View Article : Google Scholar : PubMed/NCBI
8	Willey JS, Lloyd SA, Nelson GA and Bateman TA: Ionizing radiation and bone loss: Space exploration and clinical therapy applications. Clin Rev Bone Miner Metab. 9:54–62. 2011. View Article : Google Scholar : PubMed/NCBI
9	Sparks RB, Crowe EA, Wong FC, Toohey RE and Siegel JA: Radiation dose distributions in normal tissue adjacent to tumors containing (131)I or (90)Y: The potential for toxicity. J Nucl Med. 43:1110–1114. 2002.PubMed/NCBI
10	Aoki M, Sato M, Hirose K, Akimoto H, Kawaguchi H, Hatayama Y, Ono S and Takai Y: Radiation-induced rib fracture after stereo-tactic body radiotherapy with a total dose of 54-56 Gy given in 9-7 fractions for patients with peripheral lung tumor: Impact of maximum dose and fraction size. Radiat Oncol. 10:992015. View Article : Google Scholar
11	Oest ME, Policastro CG, Mann KA, Zimmerman ND and Damron TA: Longitudinal effects of single hindlimb radiation therapy on bone strength and morphology at local and contra-lateral sites. J Bone Miner Res. 33:99–112. 2018. View Article : Google Scholar
12	Wright LE, Buijs JT, Kim HS, Coats LE, Scheidler AM, John SK, She Y, Murthy S, Ma N, Chin-Sinex HJ, et al: Single-limb irradiation induces local and systemic bone loss in a murine model. J Bone Miner Res. 30:1268–1279. 2015. View Article : Google Scholar : PubMed/NCBI
13	Zhang J, Zheng L, Wang Z, Pei H, Hu W, Nie J, Shang P, Li B, Hei TK and Zhou G: Lowering iron level protects against bone loss in focally irradiated and contralateral femurs through distinct mechanisms. Bone. 120:50–60. 2019. View Article : Google Scholar
14	Oest ME, Franken V, Kuchera T, Strauss J and Damron TA: Long-term loss of osteoclasts and unopposed cortical mineral apposition following limited field irradiation. J Orthop Res. 33:334–342. 2015. View Article : Google Scholar :
15	Sun W, Zhao C, Li Y, Wang L, Nie G, Peng J, Wang A, Zhang P, Tian W, Li Q, et al: Osteoclast-derived microRNA-containing exosomes selectively inhibit osteoblast activity. Cell Discov. 2:160152016. View Article : Google Scholar : PubMed/NCBI
16	Bazire L, Xu H, Foy JP, Amessis M, Malhaire C, Cao K, De La Rochefordiere A and Kirova YM: Pelvic insufficiency fracture (PIF) incidence in patients treated with intensity-modulated radiation therapy (IMRT) for gynaecological or anal cancer: Single-institution experience and review of the literature. Br J Radiol. 90:201608852017. View Article : Google Scholar : PubMed/NCBI
17	Uezono H, Tsujino K, Moriki K, Nagano F, Ota Y, Sasaki R and Soejima T: Pelvic insufficiency fracture after definitive radiotherapy for uterine cervical cancer: Retrospective analysis of risk factors. J Radiat Res. 54:1102–1109. 2013. View Article : Google Scholar : PubMed/NCBI
18	Wernle JD, Damron TA, Allen MJ and Mann KA: Local irradiation alters bone morphology and increases bone fragility in a mouse model. J Biomech. 43:2738–2746. 2010. View Article : Google Scholar : PubMed/NCBI
19	Rana T, Schultz MA, Freeman ML and Biswas S: Loss of Nrf2 accelerates ionizing radiation-induced bone loss by upregulating RANKL. Free Radic Biol Med. 53:2298–2307. 2012. View Article : Google Scholar : PubMed/NCBI
20	Hui SK, Fairchild GR, Kidder LS, Sharma M, Bhattacharya M, Jackson S, Le C, Petryk A, Islam MS and Yee D: The influence of therapeutic radiation on the patterns of bone remodeling in ovary-intact and ovariectomized mice. Calcif Tissue Int. 92:372–384. 2013. View Article : Google Scholar : PubMed/NCBI
21	Willey JS, Lloyd SA, Robbins ME, Bourland JD, Smith-Sielicki H, Bowman LC, Norrdin RW and Bateman TA: Early increase in osteoclast number in mice after whole-body irradiation with 2 Gy X rays. Radiat Res. 170:388–392. 2008. View Article : Google Scholar : PubMed/NCBI
22	Kondo H, Searby ND, Mojarrab R, Phillips J, Alwood J, Yumoto K, Almeida EA, Limoli CL and Globus RK: Total-body irradiation of postpubertal mice with (137)Cs acutely compromises the microarchitecture of cancellous bone and increases osteoclasts. Radiat Res. 171:283–289. 2009. View Article : Google Scholar : PubMed/NCBI
23	Lucas PA, Aubineau-Lanièce I, Lourenço V, Vermesse D and Cutarella D: Using LiF:Mg, Cu, P TLDs to estimate the absorbed dose to water in liquid water around an 192Ir brachytherapy source. Med Phys. 41:0117112014. View Article : Google Scholar
24	Fartaria MJ, Reis C, Pereira J, Pereira MF, Cardoso JV, Santos LM, Oliveira C, Holovey V, Pascoal A and Alves JG: Assessment of the mean glandular dose using LiF:Mg, Ti, LiF:Mg, Cu, P, Li₂B₄O₇:Mn and Li2B4O7:Cu TL detectors in radiation fields. Phys Med Biol. 61:6384–6399. 2016. View Article : Google Scholar : PubMed/NCBI
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
26	Bernier J, Hall EJ and Giaccia A: Radiation oncology: A century of achievements. Nat Rev Cancer. 4:737–747. 2004. View Article : Google Scholar : PubMed/NCBI
27	Jia D, Gaddy D, Suva LJ and Corry PM: Rapid loss of bone mass and strength in mice after abdominal irradiation. Radiat Res. 176:624–635. 2011. View Article : Google Scholar : PubMed/NCBI
28	Xu X, Li R, Zhou Y, Zou Q, Ding Q, Wang J, Jin W, Hua G and Gao J: Dysregulated systemic lymphocytes affect the balance of osteogenic/adipogenic differentiation of bone mesenchymal stem cells after local irradiation. Stem Cell Res Ther. 8:712017. View Article : Google Scholar : PubMed/NCBI
29	Bonewald LF: The role of the osteocyte in bone and nonbone disease. Endocrinol Metab Clin North Am. 46:1–18. 2017. View Article : Google Scholar : PubMed/NCBI
30	Willey JS, Livingston EW, Robbins ME, Bourland JD, Tirado-Lee L, Smith-Sielicki H and Bateman TA: Risedronate prevents early radiation-induced osteoporosis in mice at multiple skeletal locations. Bone. 46:101–111. 2010. View Article : Google Scholar :
31	Alwood JS, Shahnazari M, Chicana B, Schreurs AS, Kumar A, Bartolini A, Shirazi-Fard Y and Globus RK: Ionizing radiation stimulates expression of pro-osteoclastogenic genes in marrow and skeletal tissue. J Interferon Cytokine Res. 35:480–487. 2015. View Article : Google Scholar : PubMed/NCBI
32	Ren L, Song ZJ, Cai QW, Chen RX, Zou Y, Fu Q and Ma YY: Adipose mesenchymal stem cell-derived exosomes ameliorate hypoxia/serum deprivation-induced osteocyte apoptosis and osteocyte-mediated osteoclastogenesis in vitro. Biochem Biophys Res Commun. 508:138–144. 2019. View Article : Google Scholar