Mechanisms of dexamethasone-induced bone toxicity in developing bone: a single-cell perspective

Abstract

AbstractGlucocorticoids, such as dexamethasone, are essential for treating severe childhood conditions, including cancer, organ transplantation, and inflammatory disorders. However, their long-term use can impair bone development, posing risks to pediatric bone health, which is vital for lifelong skeletal integrity. A mechanistic insight on how glucocorticoids negatively impact bone could improve decision-making in patient care to improve the quality of life for pediatric cancer patients and survivors. In this study, we aimed to elucidate the molecular mechanisms underlying dexamethasone-induced bone toxicity in developing bones using single-cell transcriptomics. We treated skeletally immature C57BL/6JRj mice with dexamethasone for 28 days, and assessed the bone architecture with micro-computed tomography, and characterized bone and bone marrow cells from the femurs using single-cell RNA sequencing. Our findings revealed a marked reduction in osteoblast and chondrocyte cell populations and impaired function of pre-osteoblasts. Additionally, dexamethasone adversely affected B cell subsets, significantly depleting early B cell progenitors while allowing some further developed immature B cells to persist. These cellular changes were accompanied by reduced longitudinal bone growth, compromised bone architecture, and increased bone fragility at the highest doses of dexamethasone. Interestingly, unlike observations in adults, dexamethasone did not enhance osteoclast activity in our model. Overall, our study suggests that the adverse effects of dexamethasone on bone development are primarily due to its impact on osteoblastic, chondroblastic and B cell lineages, disrupting the critical signaling crosstalk between the cells necessary for bone development and hematopoiesis. Layman summaryGlucocorticoids, like dexamethasone, are vital for treating severe childhood illnesses but can harm bone development when used long-term. This study investigated how dexamethasone affects bone health in young mice. Using advanced techniques, we found that dexamethasone reduced key bone-building cells (osteoblasts and chondrocytes) and weakened their function. It also disrupted immune cell development in the bone marrow, especially early B cells. These changes led to weaker, more fragile bones without increasing bone breakdown, unlike in adults. The findings highlight the need to carefully balance treatment benefits and risks for children to protect their bone health and overall well-being.