Recovery from radiation-induced damage to growth plates involves functional compensation

• Background: Children receiving radiotherapy during cancer treatment are highly susceptible to side-effects including short stature, irregular body proportions and spinal curvature. One reason radiotherapy impairs bone growth is that radiation directly damages cells that are responsible for bone elongation: growth plate chondrocytes.Purpose: After irradiation, bone growth can continue to a limited extent, but the underlying mechanisms of this recovery process are poorly understood. We aimed to characterize the effects of radiation on the growth plate and reveal the cellular recovery processes.Methods: The left proximal tibia of one month-old mice was irradiated(x-ray) dorso-ventrally. The effects of radiation were characterized by measuring bone lengths and conducting immunofluorescence. Recovery was analyzed using clonal genetic tracing, imaged with confocal microscopy.Results: We first conducted an irradiation-dose-response study up to 15Gy. In our model, a single dose of 10Gy focal irradiation (with biological effective dose of 38.57Gy, equivalent to 12 fractions of 2Gy) was the lowest dose that significantly reduced bone length, fourteen days after irradiation (irradiated tibia were 96.3% the length of the contralateral control, n=5, p= 0.0036). We then used clonal genetic tracing with Col2CreERT:R26R-Confetti mice to visualize the clonal recovery one month after irradiation, and made two inter-connected observations: (i) radiation dose-dependently prevented chondrocytes from further dividing, thus reducing the number of clonal-columns (Fig.1, arrowheads), (ii) some chondrocytes dose-dependently produced an increased number of columns (Fig.1, asterisk); of the clones that did produce columns, individual clones produced a mean of 4.85 columns in the irradiated side versus 2.08 columns in the contralateral control (p<0.0001, unpaired t-test, n= minimum of 17 clones pooled from 4 mice).Conclusion: After radiation-induced damage, some growth plate chondrocytes can functionally compensate for the damaged cells and produce more than twice the expected number of columns.Ethical permission: All experiments were approved by the Swedish board of agriculture.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)

Nyckelord

cellforskning

cell research

biomedicinsk strålningsvetenskap

Biomedical Radiation Science

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