Bone-on-a-chip recapitulates dynamic bone remodeling

Bone remodeling is governed by the basic multicellular unit (BMU) and plays a crucial role in both normal bone function and pathological conditions (e.g. osteoporosis). Unfortunately, our understanding of the bone remodeling process is limited as current models do not allow dynamic events in the BMU to be systematically and spatiotemporally analyzed. Leveraging microfluidic and stem cell technologies, we developed an bone-on-a-chip model that enables the dynamic co-culture of osteoblasts (OBs) and osteoclasts (OCs) in a spatiotemporal context. This model faithfully recapitulates critical aspects of the bone remodeling process, including cell migration and differentiation into OBs and OCs, as well as their delicate coupling within the BMU during bone regeneration, homeostasis, and in osteoporotic conditions. RNA sequencing analyses revealed that our bone remodeling-on-a-chip model exhibits more pronounced osteoporotic features compared to conventional OB-OC co-cultures, closely resembling the pathological bone remodeling observed in osteoporotic mice. Notably, our bone remodeling-on-a-chip model accurately predicts the clinically observed antiresorptive effects of two anti-osteoporosis drugs. Therefore, our bone remodeling-on-a-chip model stands poised as an advanced platform to enhance our understanding of bone pathophysiology and offers a promising alternative to current drug testing in bone-related diseases. Statement of Significance Bone remodeling, governed by the basic multicellular unit (BMU), is crucial for bone development. Current models fail to analyze dynamic events within the BMU systematically and spatiotemporally. We developed a microfluidic bone remodeling-on-a-chip model for the co-culture of osteoblasts (OBs) and osteoclasts (OCs). This model replicates key aspects of bone remodeling, including the migration, differentiation, and coupling of OBs and OCs under various conditions. It closely mirrors pathological bone remodeling in osteoporotic mice and demonstrates reliable drug testing for anti-osteoporosis drugs. This advanced platform enhances our understanding of bone pathophysiology and offers a promising drug testing model for bone-related diseases.