Mechanotransduction describes the translation of mechanical cues into biological signals that fine-tune bone remodelling. On a tissue-wide level, mechanotransduction is facilitated by a dendritic network of osteocytes (OCYs) that make up 90% of bone cells 1. OCYs are responsible for tissue-wide signal integration and translation thus contributing to the adaption of bone to altered loading conditions. The interplay of the applied mechanical load and the corresponding biological activity in terms of bone formation or degradation is described in the mechanostat theory 2. While this theory accurately describes how signal input and biological output relate to each other, the inner workings of the mechanostat are not fully understood. In this context, the crosstalk between OCYs and bone-forming OBs under different loading conditions is of particular interest. It is therefore proposed to utilize state-of-the-art technologies such as organoid generation and their culture in microphysiological systems (MPS) to recreate the mechanostat (Fig.1). Two approaches based on a commercially available and a custom-made MPS will be presented. For the generation of core-shell organoids containing OCY networks, primary human OBs are embedded in a collagen hydrogel (Fig.1: A). Initial experiments confirm viability and growth of these cells, while their ALP activity is almost completely lost, indicating a loss of bone forming capabilities (Fig.1: D,E). These OCY organoids can be co-cultured with OB organoids in a commercial MPS (Fig.1: B,C). OB organoids are based on allogenic decellularized spongiosa. After cell seeding, OBs are viable and proliferate while their ALP activity remains high, confirming their bone-forming phenotype (Fig.1: E,F). In this co-culture model, mechanical cues are provided in terms of pulsatile hydrostatic pressure and shear stress thus allowing for the investigation of cell-cell communication in response to mechanical stimulation. In addition, the spatial separation of the organoids allows for organoid-specific analysis of mRNA and protein expression levels. In a next step, a biphasic organoid is cultured in a more complex custom-made MPS under defined oxygen saturation and mechanical loading (Fig.1: C). Understanding the signalling between OCYs and OBs under varying mechanical loading conditions will aid in completing the mechanostat theory, thereby finding new treatments for degenerative conditions such as osteoporosis. For any figures or tables, please contact the authors directly.
Wille et al. (Mon,) studied this question.