Fig. 8
Based on the current literature, it is reasonable to speculate that extremely low fluid shear stresses induced via microgravity, alterations in osteoporotic bone architecture, and increased adiposity will together guide cells toward a phenotype that results in osteodestruction. Hypothesized mechanisms of bone loss due to extremely reduced fluid shear stress: osteocytes release more RANKL than OPG, thereby activating osteoclastic activity and a proinflammatory macrophage phenotype. The reduced OPG and increased proinflammatory cytokine release (e.g., IL-1β, IL-6, and TNFα) and ROS suppress the osteogenic differentiation of MSCs as well as the proliferation and deposition of new bone by osteoblasts. Increased myostatin and decreased irisin expression further activate osteoclastic activity and inhibit osteoblastic activity. MSCs preferentially differentiate into adipocytes (via increased leptin and decreased adiponectin, for example) while secreting proinflammatory cytokines that contribute to maintaining the M1 macrophage phenotype. It is conceivable that the concerted response of osteocytes, osteoclasts, macrophages, adipocytes, myocytes, and MSCs, among other key cells not shown (e.g., fibroblasts and endothelial cells), will serve to keep cells within a cycle of osteodestruction. The role of mechanoresponsive HSCs remains unknown. Experimentally unconfirmed associations are labeled in green
