Fig. 2
From: Insights and implications of sexual dimorphism in osteoporosis
X-linked osteoporosis in males. X-linked osteoporosis is most likely more common in males, given the higher rates of mutation in genes, such as PLS3 and factor VIII (FVIII), that are located on the X chromosome. PLS3 deficiency induces an imbalance between bone resorption and formation, resulting in insufficient mineralization in osteoblasts, increased bone resorption in osteoclasts, and dysregulation of mechanosensing in osteocytes. A missing or defective clotting protein, factor VIII (FVIII), may directly disrupt bone homeostasis via the RANK/RANKL/OPG pathway in hemophilia A (HA) patients. The FVIII/VWF complex inhibits RANKL and increases the activity of OPG, thereby promoting osteogenesis. Activated FVIII detaches from VWF, binds to FIX, and then activates FX to FXa, which is responsible for the conversion of prothrombin into thrombin. Thrombin binds to PRL-1 to increase the production of IL-6, which further enhances the expression of RUNX2 and osteocalcin, decreasing the expression of RANKL. FVIII or FIX regulates the Wnt/β-catenin pathway and reduces the production of sclerostin to further inhibit the Wnt signaling pathway. OPG osteoprotegerin, RANKL receptor activator of nuclear factor-kappa B ligand, TNF-α tumor necrosis factor α, IFN-γ interferon-γ; IL-1β, interleukin-1β, IL-6 interleukin-6, MAPK mitogen-activated protein kinase, COX-2 cyclooxygenase 2, PGE2 prostaglandin E2, EP4 PGE2 receptor 4, RUNX2 runt-related transcription factor 2
