Apolipoprotein E as a potential regulator of osteoclast-osteoblast coupling in material-induced bone formation

Osteoinductive materials which induce bone formation in non-osseous sites are promising bone substitutes to repair critical-sized bone defects. It appears that innate immune response (esp. osteoclastogenesis) to materials plays an important role in material-induced bone formation. In this study, the coupling between osteoclastogenesis and subsequent osteogenesis in material-induced bone formation was investigated. Osteoclastogenesis of mouse bone marrow-derived monocytes (BMMs) on osteoinductive tricalcium phosphate (TCPs) and non-osteoinductive tricalcium phosphate (TCPb) ceramics were evaluated with high-throughput RNA sequencing (RNA-seq) and RT-qPCR regarding secretory proteins. It turned out that osteoinductive TCPs supported osteoclastogenesis and enhanced Apolipoprotein E (ApoE) production. Meanwhile, ApoE enhanced osteogenic gene expression (Alp, Runx2, Col1a1, Osterix) and ALP staining and activity of CRL-12424 cells in vitro. Additionally, western blot assay revealed that ApoE played its role in osteogenesis of CRL-12424 by activating JAK-STAT pathway instead of PI3K-AKT pathway. The overall data indicated that ApoE was a potential coupling factor between osteoclastogenesis and osteogenesis in material-induced bone formation. By secreting ApoE, osteoclasts formed on osteoinductive materials stimulated osteogenic differentiation of osteo-progenitors via JAK-STAT pathway. STATEMENT OF SIGNIFICANCE: Osteoinductive materials can repair critical-sized bone defects, while the precise mechanism osteoinductive materials driving bone formation remains unclear. Recent research has highlighted the role of osteoclastogenesis in material-induced bone formation, how osteoclastogenesis playing its role in osteogenesis was subjected to investigation in the current study. Robust ApoE gene expression shown in osteoclastogenesis with the osteoinductive material and ApoE enhancing osteogenesis of mesenchymal stromal cells (CRL-12424) indicated ApoE as a potential regulator of osteoclast-osteoblast coupling, providing thus novel insights into the complex interplay of cellular responses and contributing to the development of more effective bone substitute materials.