Background: Protein C (PC) is activated by thrombin complexed with thrombomodulin (TM), which is present on vascular endothelial cells. Activated PC (APC) regulates blood coagulation by inactivating the factors Va and VIIIa. We have so far demonstrated the inhibitory effect of APC on the differentiation of osteoclast precursor cells into osteoclasts via endothelial cell protein C receptor (EPCR) and PAR-1.

Aims: In the present study, to further elucidate the relationship between bone remodeling and blood coagulation, we investigated the detailed signal transduction mechanism of APC-induced suppression of osteoclast differentiation.

Methods: Normal human osteoclast precursor cells were cultured in a growth medium including soluble RANKL, M-CSF, and FBS, and on days 4 and 7, the culture medium was replaced with the same medium containing various concentrations of APC, FTY720, or APC + various substances without FBS. On day 8, TRAP-positive multinucleated cells were counted manually using a light microscope. The NF-kB and NFATc1 activation in the presence or absence of APC were evaluated using specific ELISA.

Results: APC inhibited the osteoclast differentiation, and FTY720, an agonist to the S1P receptor, had no effect on the osteoclast differentiation. However, FTY720 inhibited the APC-induced suppression of osteoclast differentiation. Similarly to anti-EPCR antibody and anti-PAR-1 antibody, anti-apoER2 antibody and recombinant apoER2 also inhibited the APC-induced suppression of osteoclast differentiation. Further, APC had no effect on NF-kB and NFATc1 activation.

Conclusions: APC suppresses human osteoclast differentiation mainly by inhibiting the formation of multinucleated cells via EPCR, PAR-1, S1P receptor and apoER2.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/various-receptors-are-related-with-the-apc-induced-suppression-of-osteoclast-differentiation/