Skin wound trauma, following high-dose radiation exposure, amplifies and prolongs skeletal tissue loss

Highlights

• Non-lethal, high-dose ionizing radiation (8 Gy) adversely impacts cancellous bone structure and cell activity by day 3.

• Skin wound trauma after radiation exposure enhances and prolongs the negative response of bone to radiation.

• The effects of skin wound trauma are not localized to the site of injury, demonstrated by deleterious effects in the femur

Abstract

The present study investigated the detrimental effects of non-lethal, high-dose (whole body) γ-irradiation on bone, and the impact that radiation combined with skin trauma (i.e. combined injury) has on long-term skeletal tissue health. Recovery of bone after an acute dose of radiation (RI; 8 Gy), skin wounding (15–20% of total body skin surface), or combined injury (RI + Wound; CI) was determined 3, 7, 30, and 120 days post-irradiation in female B6D2F1 mice and compared to non-irradiated mice (SHAM) at each time-point. CI mice demonstrated long-term (day 120) elevations in serum TRAP 5b (osteoclast number) and sclerostin (bone formation inhibitor), and suppression of osteocalcin levels through 30 days as compared to SHAM (p < 0.05). Radiation-induced reductions in distal femur trabecular bone volume fraction and trabecular number through 120 days post-exposure were significantly greater than non-irradiated mice (p < 0.05) and were exacerbated in CI mice by day 30 (p < 0.05). Negative alterations in trabecular bone microarchitecture were coupled with extended reductions in cancellous bone formation rate in both RI and CI mice as compared to Sham (p < 0.05). Increased osteoclast surface in CI animals was observed for 3 days after irradiation and remained elevated through 120 days (p < 0.01). These results demonstrate a long-term, exacerbated response of bone to radiation when coupled with non-lethal wound trauma. Changes in cancellous bone after combined trauma were derived from extended reductions in osteoblast-driven bone formation and increases in osteoclast activity.

Introduction

The recently expanded use of radioactive materials in medicine, industry, agriculture, and research increases the opportunity for radiation combined injuries (CI) to occur [1]. These combined injuries, which include exposure to ionizing radiation in addition to another trauma (i.e. skin wounds, thermal burns, hemorrhage, skeletal fractures, and traumatic brain injuries), have been prevalent in the survivors of recent and historical radiation accidents (~ 10% of the 237 victims at Chernobyl) and bombings (~ 60–70% of all victims after the bombings at Hiroshima and Nagasaki) [2], [3], [4]. First responders and survivors of a nuclear attack, nuclear accident, or exposure to a radioactive dispersal device (RDD) will likely also suffer secondary consequences related to combined injuries [5], [6]. In addition, long-duration space exploration or missions involving astronaut time on terrestrial surfaces with little to no atmosphere to shield space-relevant radiation (i.e. galactic cosmic rays or solar particle events), will expose travelers to unavoidable radiation [7], [8]. In these events, any type of traumatic injury that is sustained by a crew member, in addition to ionizing radiation exposure, could limit or impede mission success [9]. Long-term consequences of these radiation combined traumas may exacerbate the effects of the individual insult on skeletal tissue, putting those individuals at greater risk for bone atrophy and risk of skeletal fracture, yet details of the interaction between radiation and injury are unclear.

The majority of literature detailing the effects of radiation on bone illustrates the consequences to skeletal tissue following radiation therapy as a treatment for various types of cancers. Radiation therapy induces severe long-term consequences to bone, which include increased bone loss and incidence of skeletal fracture [10], [11], [12]. Previous investigations have demonstrated that focalized radiation treatment to the pelvis results in a demineralization of the bone matrix, and increases risk of hip fracture in women receiving radiation therapy for cervical cancers (65%, 66%, and 214%, respectively) as compared to patients who received other therapies (i.e. chemotherapy or surgery) [10], [13]. The predominant bone damage following whole body γ-irradiation originates from a rapid loss of trabecular bone tissue, due to rapid elevations in osteoclast activation/activity coupled with decreased osteoblast activity, resulting in reduced bone formation activity and volume lasting for months following exposure [14], [15], [16], [17], [18], [19]. Although investigations into the effects of radiation on skeletal tissue have uncovered significant evidence, to our knowledge, no known investigations detailing the effects of ionizing radiation combined with skin wound trauma on bone have been undertaken. An understanding of the long-term consequences of these two traumas on skeletal tissue is necessary to determine preventative measures that can be utilized to reduce subsequent bone loss and risk of fracture.

The goal of the present study was to define the temporal impact of high-level radiation injury, wounding, and combined injury on bone properties using a mouse model. Most importantly, our aim was to define whether the long-term effects of combined injury were more detrimental than either wounding or irradiation alone. We hypothesized that irradiation followed by skin wounding would lead to a greater degree of destruction to bone microarchitecture and enhanced deleterious effects on bone cell activity than radiation exposure or wounding alone.