Recombinant Factor VIII Fc Fusion Protein Inhibits Inflammatory Osteoclast Formation in vitro
ISTH Academy. Peters R. Jul 10, 2019; 274074; OC 75.5 Topic: Hemophilia - Basic
Robert Peters
Robert Peters
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OC 75.5

Recombinant Factor VIII Fc Fusion Protein Inhibits Inflammatory Osteoclast Formation in vitro

G. Rajani, Y.-D. Lin, K. Kis-Toth, R. Peters, J. Salas
Sanofi, Rare Blood Disorders, Waltham, United States

Main Topic: Hemophilia and Bleeding (including Transfusion)
Category: Hemophilia - Basic

Background: Decrease in bone mineral density observed in severe hemophilia A (HemA) patients suggests that the absence of FVIII activity and related bleeding episodes may contribute to perturbed bone homeostasis by creating a pro-inflammatory milieu with enhanced monocyte/macrophage-derived osteoclast formation and bone erosion. Previously we found that recombinant FVIII Fc fusion protein (rFVIIIFc)-treated human macrophages exhibit Mox/M2 regulatory phenotype with tolerogenic potential and antioxidant properties driven by NRF2 pathway-associated molecular events.
Aims: Our aim was to investigate whether rFVIIIFc treatment could modify monocyte-derived osteoclastogenesis in vitro.
Methods: Monocytes from PBMC of healthy human donors were isolated and cultured with rhM-CSF and rhRANKL to achieve osteoclast formation in the presence or absence of hIgG1, rFVIII or rFVIIIFc. Osteoclast-specific and NRF2 pathway-related genes were measured by qPCR. Osteoclast phenotype was followed by tartrate-resistant acid phosphatase (TRAP) staining and multinucleation. Function of the treated osteoclasts was examined using bone resorption assay.
Results: Monocyte-derived osteoclast development was significantly impaired in the presence of rFVIIIFc observed by TRAP staining and the absence of multinucleation. Gene and protein expression of rFVIIIFc-treated cells showed upregulation of NRF2 pathway-related molecules (NQO1, GCLC, HO-1) and subsequent downregulation of molecules involved in osteoclast formation and function (NFATC1, CATK, RANK). The bone resorption capabilities of rFVIIIFc-treated monocyte-derived osteoclasts were compromised compared to untreated, hIgG1- or rFVIII-treated cells.
Conclusions: Monocyte-derived osteoclast formation was effectively inhibited by rFVIIIFc treatment while hIgG1 or rFVIII treatment had no effect on this process in vitro. The presented data suggest that replacement therapy with the extended half-life rFVIIIFc may regulate the immune milieu in people with hemophilia toward an antioxidant and less osteoporotic state. This activity of rFVIIIFc is distinct from its role in blood coagulation and in agreement with the previously described Fc-dependent Mox/M2 macrophage polarization.

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