Bone mechanobiology, gravity and tissue engineering: effects and insights

Abstract

Bone homeostasis strongly depends on fine tuned mechanosensitive regulation signals from environmental forces into biochemical responses. Similar to the ageing process, during spaceflights an altered mechanotransduction occurs as a result of the effects of bone unloading, eventually leading to loss of functional tissue. Although spaceflights represent the best environment to investigate near-zero gravity effects, there are major limitations for setting up experimental analysis. A more feasible approach to analyse the effects of reduced mechanostimulation on the bone is represented by the 'simulated microgravity' experiments based on: (1) in vitro studies, involving cell cultures studies and the use of bioreactors with tissue engineering approaches; (2) in vivo studies, based on animal models; and (3) direct analysis on human beings, as in the case of the bed rest tests. At present, advanced tissue engineering methods allow investigators to recreate bone microenvironment in vitro for mechanobiology studies. This group and others have generated tissue 'organoids' to mimic in vitro the in vivo bone environment and to study the alteration cells can go through when subjected to unloading. Understanding the molecular mechanisms underlying the bone tissue response to mechanostimuli will help developing new strategies to prevent loss of tissue caused by altered mechanotransduction, as well as identifying new approaches for the treatment of diseases via drug testing. This review focuses on the effects of reduced gravity on bone mechanobiology by providing the up-to-date and state of the art on the available data by drawing a parallel with the suitable tissue engineering systems.

Effects of long time exposure to simulated micro- and hypergravity on skeletal architecture

“…Since years, investigators take advantage of microgravity simulation techniques that can be performed on Earth; several studies have been carried out in vitro by means of cell bioreactors and tissue engineering approaches (Pardo et al, 2005;Ko et al, 2010). A microgravity environment can be simulated on Earth through several in vivo systems, such as in the case of bed-rest tests for human volunteers (Ruggiu and Cancedda 2014;LeBlanc et al, 1987;Noble 2003;Zerwekh et al, 1998;Ziambaras et al, 2005), or hind limb unloading (HLU) test for rodents (Saxena et al, 2011;Visigalli et al, 2010). Particularly, a limited number of publications revealed that short-term mice exposition to simulated microgravity (HLU) produced a bone volume density loss similar to that observed by our long-term experimentation.…”

“…However "microgravity" is commonly used as a synonym for "unloading condition" and this paper followed this convention (Ruggiu and Cancedda 2014). Since years, investigators take advantage of microgravity simulation techniques that can be performed on Earth; several studies have been carried out in vitro by means of cell bioreactors and tissue engineering approaches (Pardo et al, 2005;Ko et al, 2010).…”

Targeted silencing of miRNA-132-3p expression rescues disuse osteopenia by promoting mesenchymal stem cell osteogenic differentiation and osteogenesis in mice

“…Throughout life, the bones are constantly remodeled by means of two coordinated and synchronized processes, including osteoblast-driven bone formation and osteoclast-driven bone resorption. This remodeling helps the bones adapt to changing loads with the optimized morphological structure and is therefore sensitive to mechanical stimulation alterations [1]. Skeletal unloading can disrupt the physiological process of bone remodeling and can induce severe bone loss, especially in weight-bearing bones.…”

Melatonin Suppresses Autophagy Induced by Clinostat in Preosteoblast MC3T3-E1 Cells

“…Microgravity during space flight leads to decreases in the mineral content of bone, bone matrix protein production and bone formation, resulting in bone loss and osteoporosis [ 13 , 14 ]. A clinostat can be used to provide valuable information about mechanotransduction as it relates to bone homeostasis in bone cells, as well as for in vitro mechanobiology studies in the bone microenvironment [ 14 , 15 ]. Maintenance of bone homeostasis is based on the regulation of biochemical responses through balancing the activities of osteoblasts, osteoclasts, and osteocytes based on mechanosensitive signal transduction from microenvironmental forces, including mechanostimulation and mechanical stress.…”