Abstract
Repetitive mechanical loading can lead to microdamage in bone tissue. In order to prevent accumulation of microdamage, a repair mechanism known as targeted bone remodeling removes the damaged bone tissue and replaces it with new bone matrix.|Osteocyte apoptosis has been associated with fatigue induced microdamage, and the localization of bone resorbing osteoclasts. However, the extracellular signals involved in the initiation of targeted bone remodeling are still unknown. While apoptosis is commonly referred to as a non-inflammatory event, inflammatory cytokines have been shown to be mediators of the bone remodeling process. To my knowledge no one has examined inflammatory cytokines in relation to fatigue induced microdamage and the targeted bone remodeling process. Therefore, in vivo fatigue loading of rat ulna was performed to identify inflammatory cytokines associated with targeted bone remodeling. Experimental results showed that fatigue loading of rat ulna results in:|1.Bone tissue microdamage.|2.Increased RANKL-percent positive osteocytes and intra-cortical osteoclasts.|3.Increased inflammatory cytokines (IL-2, GRO/KC, MCP1, VEGF) associated with the stimulation and chemotaxis of both T-cells and osteoclasts.|These results raised new questions about potential T-cell involvement in the initiation of intra-cortical osteoclasts in fatigue damaged bone tissue, and lead to the examination of a novel, mechanically-induced signaling pathway. In vitro mechanical loading was performed to examine the effects of fluid shear stress (FSS) on osteocyte production of cytokines (TGF-β1 and IL-6) known to stimulate Th17-cell secretion of osteoclastogenic cytokines (IL-17 and RANKL). Experimental results showed that:|1.MLO-Y4 osteocytes conditioned with high FSS secrete greater TGF-β1 and IL-6 compared to MLO-Y4 osteocytes in static control conditions.|2.T-cell cultures conditioned with high FSS MLO-Y4 medium secrete greater IL-17 compared to T-cell cultures conditioned with static MLO-Y4 medium.|3.Osteoclast cultures conditioned with high FSS T-cell medium form a greater number of osteoclasts compared to osteoclasts cultures conditioned with static T-cell medium.|In vitro results demonstrate a mechanically-induced osteocyte-Th17-cell signaling mechanism and subsequent osteoclast formation. With high, repetitive force required for the stimulation of the mechanism in vitro; there is potential for mechanically-induced osteocyte-Th17-cell signaling and the subsequent activation of intra-cortical osteoclasts in in vivo fatigue-loaded bone. Future in vivo fatigue loading studies examining the intra-cortical osteoclast response in relation to the described osteocyte-Th17-cell signaling mechanism would provide a new paradigm for the study and understanding of targeted bone remodeling in response to fatigue-induced microdamage.