Single-Limb Irradiation Induces Local and Systemic Bone Loss in a Murine Model

Laura Wright, Jeroen T. Buijs, Hun Soo Kim, Laura E. Coats, Anne M. Scheidler, Sutha K. John, Yun She, Sreemala Murthy, Ning Ma, Helen J. Chin-Sinex, Teresita Bellido, Ted A. Bateman, Marc Mendonca, Khalid Mohammad, Theresa Guise

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Increased fracture risk is commonly reported in cancer patients receiving radiotherapy, particularly at sites within the field of treatment. The direct and systemic effects of ionizing radiation on bone at a therapeutic dose are not well-characterized in clinically relevant animal models. Using 20-week-old male C57Bl/6 mice, effects of irradiation (right hindlimb; 2 Gy) on bone volume and microarchitecture were evaluated prospectively by microcomputed tomography and histomorphometry and compared to contralateral-shielded bone (left hindlimb) and non-irradiated control bone. One week postirradiation, trabecular bone volume declined in irradiated tibias (-22%; p<0.0001) and femurs (-14%; p=0.0586) and microarchitectural parameters were compromised. Trabecular bone volume declined in contralateral tibias (-17%; p=0.003), and no loss was detected at the femur. Osteoclast number, apoptotic osteocyte number, and marrow adiposity were increased in irradiated bone relative to contralateral and non-irradiated bone, whereas osteoblast number was unchanged. Despite no change in osteoblast number 1 week postirradiation, dynamic bone formation indices revealed a reduction in mineralized bone surface and a concomitant increase in unmineralized osteoid surface area in irradiated bone relative to contralateral and non-irradiated control bone. Further, dose-dependent and time-dependent calvarial culture and in vitro assays confirmed that calvarial osteoblasts and osteoblast-like MC3T3 cells were relatively radioresistant, whereas calvarial osteocyte and osteocyte-like MLO-Y4 cell apoptosis was induced as early as 48 hours postirradiation (4 Gy). In osteoclastogenesis assays, radiation exposure (8 Gy) stimulated murine macrophage RAW264.7 cell differentiation, and coculture of irradiated RAW264.7 cells with MLO-Y4 or murine bone marrow cells enhanced this effect. These studies highlight the multifaceted nature of radiation-induced bone loss by demonstrating direct and systemic effects on bone and its many cell types using clinically relevant doses; they have important implications for bone health in patients treated with radiation therapy.

Original languageEnglish
Pages (from-to)1268-1279
Number of pages12
JournalJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume30
Issue number7
DOIs
StatePublished - Jul 1 2015

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Extremities
Bone and Bones
Osteoblasts
Osteocytes
Hindlimb
Tibia
Osteogenesis
Femur
Radiotherapy
X-Ray Microtomography
Adiposity
Osteoclasts
Coculture Techniques
Ionizing Radiation
Bone Marrow Cells
Cell Differentiation
Animal Models
Bone Marrow
Macrophages
Radiation

Keywords

  • MARROW ADIPOSITY
  • MICROARCHITECTURE
  • OSTEOBLAST
  • OSTEOCLASTS
  • OSTEOCYTE
  • RADIATION

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Single-Limb Irradiation Induces Local and Systemic Bone Loss in a Murine Model. / Wright, Laura; Buijs, Jeroen T.; Kim, Hun Soo; Coats, Laura E.; Scheidler, Anne M.; John, Sutha K.; She, Yun; Murthy, Sreemala; Ma, Ning; Chin-Sinex, Helen J.; Bellido, Teresita; Bateman, Ted A.; Mendonca, Marc; Mohammad, Khalid; Guise, Theresa.

In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Vol. 30, No. 7, 01.07.2015, p. 1268-1279.

Research output: Contribution to journalArticle

Wright, Laura ; Buijs, Jeroen T. ; Kim, Hun Soo ; Coats, Laura E. ; Scheidler, Anne M. ; John, Sutha K. ; She, Yun ; Murthy, Sreemala ; Ma, Ning ; Chin-Sinex, Helen J. ; Bellido, Teresita ; Bateman, Ted A. ; Mendonca, Marc ; Mohammad, Khalid ; Guise, Theresa. / Single-Limb Irradiation Induces Local and Systemic Bone Loss in a Murine Model. In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2015 ; Vol. 30, No. 7. pp. 1268-1279.
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AU - Chin-Sinex, Helen J.

AU - Bellido, Teresita

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AU - Mohammad, Khalid

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N2 - Increased fracture risk is commonly reported in cancer patients receiving radiotherapy, particularly at sites within the field of treatment. The direct and systemic effects of ionizing radiation on bone at a therapeutic dose are not well-characterized in clinically relevant animal models. Using 20-week-old male C57Bl/6 mice, effects of irradiation (right hindlimb; 2 Gy) on bone volume and microarchitecture were evaluated prospectively by microcomputed tomography and histomorphometry and compared to contralateral-shielded bone (left hindlimb) and non-irradiated control bone. One week postirradiation, trabecular bone volume declined in irradiated tibias (-22%; p<0.0001) and femurs (-14%; p=0.0586) and microarchitectural parameters were compromised. Trabecular bone volume declined in contralateral tibias (-17%; p=0.003), and no loss was detected at the femur. Osteoclast number, apoptotic osteocyte number, and marrow adiposity were increased in irradiated bone relative to contralateral and non-irradiated bone, whereas osteoblast number was unchanged. Despite no change in osteoblast number 1 week postirradiation, dynamic bone formation indices revealed a reduction in mineralized bone surface and a concomitant increase in unmineralized osteoid surface area in irradiated bone relative to contralateral and non-irradiated control bone. Further, dose-dependent and time-dependent calvarial culture and in vitro assays confirmed that calvarial osteoblasts and osteoblast-like MC3T3 cells were relatively radioresistant, whereas calvarial osteocyte and osteocyte-like MLO-Y4 cell apoptosis was induced as early as 48 hours postirradiation (4 Gy). In osteoclastogenesis assays, radiation exposure (8 Gy) stimulated murine macrophage RAW264.7 cell differentiation, and coculture of irradiated RAW264.7 cells with MLO-Y4 or murine bone marrow cells enhanced this effect. These studies highlight the multifaceted nature of radiation-induced bone loss by demonstrating direct and systemic effects on bone and its many cell types using clinically relevant doses; they have important implications for bone health in patients treated with radiation therapy.

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