Fig. 1
The regulation of FVIII, FIX, thrombin, and cytokines in bone metabolism. FVIII regulates bone homeostasis through the RANK/RANKL/OPG axis. The FVIII/VWF complex binds to RANKL and OPG, inhibits RANKL-induced osteoclastogenesis, and enhances the inhibitory effects of OPG on osteoclasts, thereby promoting osteogenesis. Another possible factor that regulates bone metabolism is thrombin. Activated FVIII detaches from VWF and forms a complex with activated FIX, which further activates FX. FXa catalyzes the conversion of prothrombin into thrombin. Thrombin regulates bone metabolism by binding to PAR-1 on osteoblast membranes, which further upregulates the expression of IL-6. Upregulated IL-6 stimulates the expression of RUNX2 and osteocalcin and reduces the expression of RANKL, further reducing osteoclastogenesis. Cytokines produced from recurrent intra-articular bleeding are also involved in bone metabolism. TNF-α, IFN-γ, IL-1β, etc., directly increase the expression RANKL, resulting in increased bone resorption. On the other hand, FVIII or FIX regulates bone metabolism through the Wnt/β-catenin pathway. FVIII or FIX might decrease the levels of sclerostin, further attenuating the inhibitory effect of sclerostin on the Wnt signaling pathway and thus promoting bone formation. AKT, PI3K-protein kinase B; COX-2, cyclooxygenase 2; EP4, PGE2 receptor 4; IFN-γ, interferon-γ; IL-1β, interleukin-1β; IL-6, interleukin-6; MAPK, mitogen-activated protein kinase; OC, osteocalcin; OPG, osteoprotegerin; PAR-1, protease-activated receptor 1; PGE2, prostaglandin E2; PI3K, phosphoinositide 3-kinase; RANK, receptor activator of nuclear factor-kappa B; RANKL, receptor activator of nuclear factor-kappa B ligand; RUNX2, runt-related transcription factor 2; TNF-α: tumor necrosis factor α