Fabp5+ Foamcell As Osteoclast Progenitor Drives Biomaterial-Induced Bone Formation

Osteoinductive biomaterial is a promising therapeutic approach for repairing large jaw bone defects. However, the mechanism behind remains largely unknown. Here, we demonstrated a link between foam macrophage, osteoclastogenesis, and osteoinductive biomaterial-induced bone formation. Pseudotime trajectory analysis of scRNA-seq demonstrated that the expression of Fabp5 (a foam cell marker) was prior to Ctsk (an osteoclast marker) during the process of osteoclastogenesis, and their co-localization was confirmed by dual immunofluorescence, suggesting foam cells may serve as osteoclast precursors‌. The intramuscular implantation of an osteoinductive material in APOE-/- mice with higher lipid phagocytosis resulted in more osteoclasts at week 2 and increased bone formation after week 4 compared with the results obtained in C57 mice. Similarly, in vitro, monocytes derived from APOE-/- mice formed more osteoclasts than those derived from C57 mice. Moreover, the in vitro results showed that ox-LDL-induced foam cell formation in C57BL/6-derived macrophages markedly enhanced osteoclastogenesis. Consistently, the local injection of ox-LDL in intramuscular implantation site significantly enhanced more osteoclastogenesis in the osteoinductive biomaterial. Transcriptomic analysis revealed that macrophage lipid accumulation enhanced osteoclast formation through the RAP1/ERK axis, confirmed by related inhibitors. The current findings would provide new insights into the design of more effective osteoinductive biomaterials and the treatment of pathologic heterotopic bone formation. Furthermore, considering that atherosclerosis (AS) as an example of pathologic heterotopic bone formation and foam cells drive AS, our study also offers new insights for the treatment of AS.