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In vitro evaluation of potential biomedical strategies aimed to prevent bone loss during spaceflight

In vitro evaluation of potential biomedical strategies aimed to prevent bone loss during spaceflight 2017-2019
Acronym: SPACEBONE
Project director: Stefana-Maria Petrescu

Bone loss represents one of the most important health problems experienced by Space travelling astronauts. Microgravity produces deterioration of the skeleton due to lack of mechanical loading thus affecting both muscle and bones. Tendons stiffness decreases, muscle fibres atrophies and attenuates their metabolic capacity, whileprogressive cartilage loss occurs.

Bone loss represents one of the most important health problems experienced by Space travelling astronauts. Microgravity produces deterioration of the skeleton due to lack of mechanical loading thus affecting both muscle and bones. Tendons stiffness decreases, muscle fibres atrophies and attenuates their metabolic capacity, whileprogressive cartilage loss occurs.
Space explorers experience significant bone mass decrease (1 - 1.5 % bone mass loss each month, spaceflight osteopenia) which leads to bone fragility similar to what occurson Earth and known asosteoporosis. Noteworthy, tibia is irreversibly affected. Also, due to decreased mechanic forces, the spine lengthens up to 7 cm. Consequently, crew members experience back pain, risks of kidney stones accumulation and bone fractures together with impaired fracture healing.

Current treatments and adopted countermeasures fail to reverse the damaging effects of microgravity exposure on bone mineral content. Limited efficacy is reported for bisphosphonates - the only used chemical treatment of bone loss. Current treatments and adopted countermeasures fail to reverse the damaging effects of microgravity exposure on bone mineral content.

The aim of this project is to evaluate the potential of FGF2 to counteract bone degeneration in Space residents with the long-term goal to contribute to development of more effective treatments for Space osteopenia. In our project we will design and develop methodologies to assess FGF2 optimal dosage and temporal administration protocol for enhancing osteoblast differentiation from progenitor cells exposed to simulated microgravity.

Stefana-Maria Petrescu, Dr.
Stefana-Maria Petrescu, Dr.

Director of Institute, Head of Department

Dr. Petrescu graduated from the Department of Biochemistry, University of Bucharest and obtained a PhD in Biology from the Romanian Academy. She was a DAAD fellow and FEBS fellowship recipient at University of Wurzburg, Germany, during 1990. She followed postdoctoral studies in the Department of Biochemistry at the University of Oxford, UK. She obtained three consecutive Wellcome Trust Grants in collaboration with the University of Oxford from 1995- 2004. She investigated the glycobiology of tyrosinase from melanoma cells contributing to the fundamental mechanisms of calnexin associated folding and quality control of glycoproteins. She proposed tyros More...

The proposed project is designed at the interface of Space Biomedicine and Bone Research. As principal goal of our research, we aim to investigate potential positive effect of fibroblast growth factor2 (FGF2) on osteogenic differentiation of mesenchymal stem cells (MSC) before, during or after exposure to microgravity (μ-g), as potential therapeutic approach to prevent the loss of bone mineral content during spaceflight.

More specifically, our proposed research activity consists of four main objectives:

  1. To perform an extensive survey and review of the domain literature and to propose appropriate experimental design for research tests.;
  2. To analyse the FGF2 effect on MSCs differentiation to osteoblasts in 3D versus 2D growth, under concomitant exposure to pro-adipogenic and pro-osteogenic conditions, in normal g and μ-g conditions.
  3. To favour/enhance the reversion of microgravity-induced MSCs low-differentiating phenotype - by in vitro mimicked mechanical loading,
  4. To investigate the potential of FGF2 to prevent or treat bone loss,
Project Director Stefana Petrescu, PhD - IBAR
Researcher Chiritoiu Gabriela, PhD - IBAR
Researcher Petreuta Alexandru, PhD - IBAR
Researcher Livia Sima, PhD - IBAR
MSc student Sulea Teodor-Azavatur - IBAR
Head P1 Vizitiu Cristian - ISS
Syst.Eng. Valeanu Vlad - ISS
Biophysicist de Hillerin Pierre - ISS
Biophysicist Nistorescu Alexandru - ISS
Syst.Eng. Dinculescu Adrian - ISS
Syst.Eng. Marin Mihaela - ISS
Recovery Eval. Marin Calin - ISS
Head P2 Sima Felix - INFLPR
Researcher Axente Emanuel - INFLPR
Researcher Jipa Florin - INFLPR
MSc Iosub Stefana - INFLPR
Researcher Dinca Valentina - INFLPR
Physicist Anca Bonciu - INFLPR
Rerearcher Rusen Laurentiu - INFLPR

The expected impact of our studies on space research is to gather supplemental knowledge into adult osteogenic stem cells differentiation potential in low gravity conditions, where it is known that the balance is shifted toward the production of fat tissue rather than bone. At the end of the project we expect to find if microgravity affects response of bone progenitor cells to a growth factor, FGF2, which we have shown to enhance mineralization of osteoinduced cells in normal gravity. An important result would be to reveal that FGF2 regulates the transcriptional program of human mesenchymal stem cells in bone marrow in favor of osteogenic differentiation and thus it could be considered a potential drug for treatment of space osteopenia in astronauts.

Moreover, our RPM-simulated microgravity model will represent a platform for further drug screening that would reduce the need for animal testing. Any drug aimed to treat bone degenerative diseases, could be hence evaluated to test its effect on osteoblast differentiation upon cultivation of cell progenitors in the absence of mechanical loading.

This discovery would impact also basic research in the field of bone development as our model of investigating cell differentiation in simulated microgravity conditions could further be used to study the transcriptional responsiveness of MSCs to environmental changes through epigenetic mechanism. In the last ten years progress has been achieved in understanding how epigenetic mechanisms mediate adaptation of cells and organisms to received stimuli. Cell developments of healthy organisms as well as apparition of diseases are controlled by epigenetic mechanisms. In our model, FGF2-induced signalling and mechanotransduction of loading stimuli represent potential triggers of gene expression modifications that could alter the multipotent capacity and differentiation of MSCs. These would represent further ground research directions that would expand the molecular and cell biology expertise in IB-AR.

Contrary of what occurs upon bone deformation, the mechanical stimulation of new bone formation is impeded around implants, which support almost all loading on the affected skeletal part. If using FGF2 and/or specific microtopografies we contribute to increase in mechanotransduction we could further apply this in medical prosthetics to tiate the design of implants with increased capacity of osseointegration for astronauts in space (e.g. more resistant dental implants) or patients on Earth.

Opening new research avenues in the field of epigenetic control of bone health is expected to attract students in the field of cell and molecular biology as well as medical engineering, thus creating a niche of educating the young researchers in the proposing organization(s).

Moreover, training in the use of RPM could help as develop alternatives to generate cancer cells spheroids for melanoma research in IBAR.