A novel multifunctional radioprotective strategy using P7C3 as a countermeasure against ionizing radiation-induced bone loss

Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone.Presently,no effective countermeasure exists,and ionizing radiation-induced bone damage continues to be a substantial source of pain and morbidity.The purpose of this study was to investigate a small molecule aminopropyl carbazole named P7C3 as a novel radioprotective strategy.Our studies revealed that P7C3 repressed ionizing radiation(IR)-induced osteoclastic activity,inhibited adipogenesis,and promoted osteoblastogenesis and mineral deposition in vitro.We also demonstrated that rodents exposed to clinically equivalent hypofractionated levels of IR in vivo develop weakened,osteoporotic bone.However,the administration of P7C3 significantly inhibited osteoclastic activity,lipid formation and bone marrow adiposity and mitigated tissue loss such that bone maintained its area,architecture,and mechanical strength.Our findings revealed significant enhancement of cellular macromolecule metabolic processes,myeloid cell differentiation,and the proteins LRP-4,TAGLN,ILK,and Tollip,with downregulation of GDF-3,SH2B1,and CD200.These proteins are key in favoring osteoblast over adipogenic progenitor differentiation,cell matrix interactions,and shape and motility,facilitating inflammatory resolution,and suppressing osteoclastogenesis,potentially via Wnt/β-catenin signaling.A concern was whether P7C3 afforded similar protection to cancer cells.Preliminarily,and remarkably,at the same protective P7C3 dose,a significant reduction in triple-negative breast cancer and osteosarcoma cell metabolic activity was found in vitro.Together,these results indicate that P7C3 is a previously undiscovered key regulator of adipo-osteogenic progenitor lineage commitment and may serve as a novel multifunctional therapeutic strategy,leaving IR an effective clinical tool while diminishing the risk of adverse post-IR complications.Our data uncover a new approach for the prevention of radiation-induced bone damage,and further work is needed to investigate its ability to selectively drive cancer cell death.

Changes in interstitial fluid flow,mass transport and the bone cell response in microgravity and normogravity

In recent years,our scientific interest in spaceflight has grown exponentially and resulted in a thriving area of research,with hundreds of astronauts spending months of their time in space.A recent shift toward pursuing territories farther afield,aiming at near-Earth asteroids,the Moon,and Mars combined with the anticipated availability of commercial flights to space in the near future,warrants continued understanding of the human physiological processes and response mechanisms when in this extreme environment.Acute skeletal loss,more severe than any bone loss seen on Earth,has significant implications for deep space exploration,and it remains elusive as to why there is such a magnitude of difference between bone loss on Earth and loss in microgravity.The removal of gravity eliminates a critical primary mechano-stimulus,and when combined with exposure to both galactic and solar cosmic radiation,healthy human tissue function can be negatively affected.An additional effect found in microgravity,and one with limited insight,involves changes in dynamic fluid flow.Fluids provide the most fundamental way to transport chemical and biochemical elements within our bodies and apply an essential mechano-stimulus to cells.Furthermore,the cell cytoplasm is not a simple liquid,and fluid transport phenomena together with viscoelastic deformation of the cytoskeleton play key roles in cell function.In microgravity,flow behavior changes drastically,and the impact on cells within the porous system of bone and the influence of an expanding level of adiposity are not well understood.This review explores the role of interstitial fluid motion and solute transport in porous bone under two different conditions:normogravity and microgravity.

A novel approach for the prevention of ionizing radiation-induced bone loss using a designer multifunctional cerium oxide nanozyme

The disability,mortality and costs due to ionizing radiation(IR)-induced osteoporotic bone fractures are sub-stantial and no effective therapy exists.Ionizing radiation increases cellular oxidative damage,causing an imbalance in bone turnover that is primarily driven via heightened activity of the bone-resorbing osteoclast.We demonstrate that rats exposed to sublethal levels of IR develop fragile,osteoporotic bone.At reactive surface sites,cerium ions have the ability to easily undergo redox cycling:drastically adjusting their electronic con-figurations and versatile catalytic activities.These properties make cerium oxide nanomaterials fascinating.We show that an engineered artificial nanozyme composed of cerium oxide,and designed to possess a higher fraction of trivalent(Ce^(3+))surface sites,mitigates the IR-induced loss in bone area,bone architecture,and strength.These investigations also demonstrate that our nanozyme furnishes several mechanistic avenues of protection and selectively targets highly damaging reactive oxygen species,protecting the rats against IR-induced DNA damage,cellular senescence,and elevated osteoclastic activity in vitro and in vivo.Further,we reveal that our nanozyme is a previously unreported key regulator of osteoclast formation derived from macrophages while also directly targeting bone progenitor cells,favoring new bone formation despite its exposure to harmful levels of IR in vitro.These findings open a new approach for the specific prevention of IR-induced bone loss using synthesis-mediated designer multifunctional nanomaterials.