A Robust Microphysiological System for Mechanistic Investigation of Fat-bone Crosstalk in Diabetes
The increased risk of fragility fractures (fractures that occur from minimal trauma) has recently been recognized as a significant complication of type diabetes (T2D). Of note, T2D subjects display a lower bone turnover, which causes defective repair and increased bone damage accumulation, both leading to higher fracture risk. Given the complexity of diabetes, no single factor or pathway has been identified to govern T2D-induced bone fragility. Recently, factors produced by the adipose tissue, adipokines, have drawn more attention due to often observed fat dysfunction in T2D. However, the mechanism between the changes of adipokine level and the altered bone property is unknown, necessitating a valid and robust experimental disease model. In this study, we will create a human micro-adipose (µAD)/micro-bone (µBO) tissue chip, which will provide a model to study the interplay between these two tissues in T2D, and also serve as a high-throughput platform for specialized drug screening. Specially, µAD and µBO tissues will be housed in a customized bioreactor and microfluidically connected to each other. With this novel tissue chip, we hypothesize that the dysfunction of adipose tissues in T2D will result in diminished bone turnover. Given the importance of adiponectin (one type of adipokines) on bone health, we also hypothesize that increasing adiponectin expression by pharmacologically enhancing T2D adipose health will improve the bone turnover, thus reducing T2D-induced bone fragility. In Aim 1, we will use NORMAL human cells to engineer µADs/µBOs tissue chip in vitro, and define the impact of fat on the health of bone under normal situation. In particular, adiponectin targeting antibody (or siRNA) will be introduced to decrease the adiponectin level in the system, to examine the direct impact of adiponectin on bone. The health of µBO will be assessed by analyzing the expression of bone turnover markers, as well as the cell phenotype osteoblasts and osteoclasts in µBO. In Aim 2, we will investigate the impact of T2D µADs on the health of µBOs, and test the applicability of targeting adipose tissues as a new treatment strategy for T2D-associated bone fragility. Thiazolidinedione (TZD),one type of widely used medications in the management of T2D, will be used to improve the health of T2D adipose tissues. We will connect TZD-treated T2D µAD with µBos, or initiate the direct TZD treatment in situ, to assess the effect of enhancing adipose health on the bone health. Because of the novel dual-flow design, TZD will not be directly applied to µBO, thus eliminating its negative effect on bone quality. If we find adiponectin can significantly affect bone health in Aim 1, we will also test the application of adiponectin into T2D µADs/µBOs system. This pilot study will be conducted at the University of Pittsburgh (PITT; PI: Dr. Hang Lin) and Tulane University (Tulane; Co-PI: Dr. Bruce Bunnell). Dr. Lin has significant experience in bone tissue engineering and bioreactor culture, and Dr. Bunnell is an expert in adipose biology and pathology. Information gained from studying such an integrated tissue chip will allow the elucidation of the mechanisms by which T2D results in bone fragility. This information will also be invaluable in assessing to-be-discovered candidate medications.