(T1358) Integrating single-cell RNA-seq and spatial transcriptomics reveals the role of MMP14 as an immune-related regulator for endochondral bone integrity
Postdoctoral Fellow The University of Hong Kong Hong Kong, Hong Kong
Abstract: Hypertrophic chondrocytes (HCs) in the growth plate contribute to endochondral bone growth by continuing to differentiate, giving rise to osteoblasts in trabecular bone and adipocytes in the bone marrow. Precise regulation of the HC differentiation program is critical for their proper lineage continuum. In this study, we found that the loss of MMP14 in HCs and its descendants led to a decrease in trabecular bone in adult mice, while cortical bone and bone marrow adipose tissue were unaffected. Further analysis revealed a decrease in HC-derived osteoblasts in Mmp14 cKO mice, suggesting that Mmp14 is necessary for maintaining chondrocyte-osteoblast lineage continuum and skeletal stem and progenitor cells (SSPCs) in adult mice. Single-cell RNA sequencing, spatial transcriptome analysis and protein omics analysis identified alterations in major signaling pathways involved in bone development, including extracellular matrix organization, TGF-β signaling, and TNF signaling. The TGF-β signaling pathway was found to be disrupted, with decreased expression of its target genes. Additionally, an increase in neutrophils was observed in Mmp14 cKO mice, which was further confirmed by spatial transcriptomics. The activation of neutrophils was detected in the hypertrophic zone-trabecular region and bone marrow of Mmp14 cKO mice. Cell-cell interactions between immature neutrophils and osteogenic cells were identified, suggesting a potential role of these interactions in bone loss. Overall, this study provides insights into the role of Mmp14 in maintaining bone homeostasis and highlights the importance of HC-derived cells in bone formation and immune regulation.
