Tissue Factor-inhibited Beclin1-autophagy via BCL2 overexpression suppresses the differentiation of human monocytes into mature osteoclasts

Tissue Factor (TF) can inhibit osteoclastogenesis. Moderate autophagy is an essential factor for osteoclastogenesis. As a molecule present in human monocytes, TF can inhibit autophagic activity through B-cell lymphoma-2 (BCL2) overexpression; this suggests that the anti-osteoclastogenic role of TF may occur in human monocytes and be associated with BCL2-dependent autophagy. Our study aimed to explore the relationship between TF-regulated BCL2-autophagy signaling and osteoclast-differentiation fate of human monocytes. Cell enrichment based on fluorescence-activated cell sorting (FACS) was used to enrich TF-associated monocytic clusters. Then, a series of functional assays were performed to investigate the roles of TF in monocytic parameters associated with osteoclast precursors (OCPs). The results showed that under osteoclastic induction, the osteoclastogenic ability and autophagic activity in enriched TF^- monocytes were enhanced whereas TF⁺ monocytes exhibited opposite results. BCL2 expression and the interaction between BCL2-Beclin1 in TF^- monocytes decreased while those of TF⁺ monocytes were contrary. The osteoclastogenic ability of TF^- monocytes decreased again with autophagy inhibition with Beclin1 underexpression. The osteoclastogenic ability of TF⁺ monocytes increased again with enhanced autophagy with BCL2 inhibition and Beclin1 overexpression. Overall, TF increases BCL2-Beclin1 stability by upregulating BCL2 expression, thereby decreasing Beclin1-dependent autophagy and subsequent monocytic osteoclastogenesis in human monocytes.

Keywords:
Tissue Factor; osteoclast; monocyte; bcl2; autophagy