Hemophilia is a rare, X-linked recessive inherited bleeding disorder characterized by deficiency of coagulation factor VIII or factor IX activity. It has been associated with low bone mineral density (BMD) potentially due to predisposing factors that include physical inactivity caused by hemophilic arthropathy, vitamin D deficiency and other comorbidities such as HCV/HIV infection. Decreases 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 activity and bone erosion. Dr. Robert Peters and colleagues had previously reported that recombinant FVIII Fc fusion protein (rFVIIIFc)-treatment skewed human monocyte-derived macrophages towards a Mox/M2 regulatory phenotype with tolerogenic potential and antioxidant properties driven by NRF2 pathway-associated molecular events. As Peters mentioned, it was their aim to “investigate whether rFVIIIFc treatment could also modify monocyte-derived osteoclastogenesis in vitro.”
Peters and team isolated and cultured monocytes from peripheral blood mononuclear cells PBMC from healthy human donors using rhM-CSF and rhRANKL, and observed that monocyte-derived osteoclast morphology development was significantly impaired in the presence of rFVIIIFc compared to vehicle controls. In addition, gene and protein expression of rFVIIIFc-treated cells showed upregulation of the antioxidant NRF2 pathway-related molecules (NQO1, GCLC, HO-1) as well as downregulation of molecules involved in osteoclast formation and function (NFATC1, CATK, RANK). The bone resorption capabilities of rFVIIIFc-treated monocyte-derived osteoclasts were also compromised. Interestingly, none of these changes were found with hIgG1- or rFVIII-treated cells, only with rFVIIIFc, and these changes were not observed with mutated rFVIIIFc that lacked Fc-gamma receptor binding capacity.
Peters concluded that “Monocyte-derived osteoclast formation was effectively inhibited by rFVIIIFc treatment while hIgG1 or rFVIII treatment had no effect on this process in vitro. These in vitro data suggest that replacement therapy with the extended half-life rFVIIIFc may have potential immunoregulatory benefits on bone health in hemophilia patients.”