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Radiation-induced changes to bone composition extend beyond periosteal bone.

ABSTRACT: Background:Cancer patients receiving radiotherapy for soft tissue sarcomas are often at risk of post-irradiation (post-RTx) bone fragility fractures, but our understanding of factors controlling radiation-induced bone injury is limited. Previous studies have evaluated post-RTx changes to cortical bone composition in the periosteum of irradiated tibiae, but have not evaluated effects of irradiation in deeper tissues, such as endosteal or mid-cortical bone, and whether there are differential spatial effects of irradiation. In this study, we hypothesize that post-RTx changes to cortical bone composition are greater in endosteal compared to mid-cortical or periosteal bone. Methods:A pre-clinical mouse model of limited field hindlimb irradiation was used to evaluate spatial and temporal post-RTx changes to the metaphyseal cortex of irradiated tibiae. Irradiation was delivered unilaterally to the hindlimbs of 12-wk old female BALB/cJ mice as 4 consecutive daily doses of 5 Gy each. RTx and non-RTx tibiae were obtained at 0, 2, 4, 8, and 12 wks post-RTx (n = 9 mice/group/time). Raman spectroscopy was used to evaluate spatial and temporal post-RTx changes to cortical bone composition in age-matched RTx and non-RTx groups. Results:Significant early spatial differences in mineral/matrix and collagen crosslink ratios were found between endosteal and periosteal or mid-cortical bone at 2-wks post-RTx. Although spatial differences were transient, mineral/matrix ratios significantly decreased and collagen crosslink ratios significantly increased with post-RTx time throughout the entire tibial metaphyseal cortex. Conclusions:Irradiation negatively impacts the composition of cortical bone in a spatially-dependent manner starting as early as 2-wks post-RTx. Long-term progressive post-RTx changes across all cortical bone sites may eventually contribute to the increased risk of post-RTx bone fragility fractures.

SUBMITTER: Mandair GS

PROVIDER: S-EPMC7125315 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Radiation-induced changes to bone composition extend beyond periosteal bone.

Mandair Gurjit S GS Oest Megan E ME Mann Kenneth A KA Morris Michael D MD Damron Timothy A TA Kohn David H DH

Bone reports 20200328

<h4>Background</h4>Cancer patients receiving radiotherapy for soft tissue sarcomas are often at risk of post-irradiation (post-RTx) bone fragility fractures, but our understanding of factors controlling radiation-induced bone injury is limited. Previous studies have evaluated post-RTx changes to cortical bone composition in the periosteum of irradiated tibiae, but have not evaluated effects of irradiation in deeper tissues, such as endosteal or mid-cortical bone, and whether there are differenti ...[more]

PMID: 32258252

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Project description:Mechanical loading stimulates bone formation. Bone-lining-cell activation and cell proliferation have been implicated in this process. However, the origin of osteoblasts that form bone following mechanical stimulation remains unknown. Our objective was to identity the contributions of activation, differentiation, and proliferation of osteoblast lineage cells to loading-induced periosteal bone formation. Tamoxifen-inducible Osx-Cre-ERT2;Ai9/TdTomato reporter mice (male and female) were aged to young adult (5 months) and middle age (12 months), and were administered tamoxifen for 5 consecutive days to label osterix-lineage cells. Following a 3-week clearance period, mice were subjected to five consecutive bouts of unilateral axial tibial compression. We first confirmed this protocol stimulated an increase in periosteal bone formation that was primarily lamellar apposition. Next, mice received 5-bromo-2'-deoxyuridine (BrdU) in their drinking water daily to label proliferating cells; calcein was given to label active mineralizing surfaces. Tibias were harvested after the fifth loading day and processed for frozen undecalcified histology. The middiaphyseal periosteal surface in the region of peak bone formation was analyzed. Histology revealed both nonloaded and loaded tibias were covered in osterix positive (Osx+) cells on the periosteal surface of both 5- and 12-month-old animals. There was a significant increase in the mineralizing surface (calcein+) covered with Osx+ cells in loaded versus control limbs. Furthermore, nearly all of the mineralizing surfaces (>95%) were lined with Osx+ cells. We also observed approximately 30% of Osx+ cells were also BrdU+, indicating they arose via proliferation. These results show that following mechanical loading, pre-existing cells of the Osx lineage cover the vast majority of surfaces where there is active loading-induced bone formation, and a portion of these cells proliferated in the 5-day loading period. We conclude the initial anabolic response after mechanical loading is based on the activation and proliferation of Osx lineage cells, not the differentiation of progenitor cells. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Project description:INTRODUCTION:Aminocaproic acid is approved as an anti-fibrinolytic for use in joint replacement and spinal fusion surgeries to limit perioperative blood loss. Previous animal studies have demonstrated a pro-osteogenic effect of aminocaproic acid in spine fusion models. Here, we tested if aminocaproic acid enhances appendicular bone healing and we sought to uncover the effect of aminocaproic acid on osteoprogenitor cells (OPCs) during bone regeneration. METHODS:We employed a well-established murine femur fracture model in adult C57BL/6J mice after receiving two peri-operative injections of aminocaproic acid. Routine histological assays, biomechanical testing and micro-CT analyses were utilized to assess callus volume, and strength, progenitor cell proliferation, differentiation, and remodeling in vivo. Two disparate ectopic transplantation models were used to study the effect of the growth factor milieu within the early fracture hematoma on osteoprogenitor cell fate decisions. RESULTS:Aminocaproic acid treated femur fractures healed with a significantly smaller cartilaginous callus, and this effect was also observed in the ectopic transplantation assays. We hypothesized that aminocaproic acid treatment resulted in a stabilization of the early fracture hematoma, leading to a change in the growth factor milieu created by the early hematoma. Gene and protein expression analysis confirmed that aminocaproic acid treatment resulted in an increase in Wnt and BMP signaling and a decrease in TGF-?-signaling, resulting in a shift from chondrogenic to osteogenic differentiation in this model of endochondral bone formation. CONCLUSION:These experiments demonstrate for the first time that inhibition of the plasminogen activator during fracture healing using aminocaproic acid leads to a change in cell fate decision of periosteal osteoprogenitor cells, with a predominance of osteogenic differentiation, resulting in a larger and stronger bony callus. These findings may offer a promising new use of aminocaproic acid, which is already FDA-approved and offers a very safe risk profile.

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Radiation-induced changes to bone composition extend beyond periosteal bone.

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Radiation-induced changes to bone composition extend beyond periosteal bone.

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