C - Michigan Technological University

fluid shear on the osteocytes stimulating mechanosensory receptors [25]. Theconvective fluid flow also provides nutrients to the cells. When an osteocyte no longersenses cyclic loading, it undergoes apoptosis due to nutrient starvation and lack ofmechanical stimulation [22, 37, 38]. The apoptotic osteocytes initiate the osteoclasticresorption of bone, probably through a pro-resorptive signaling cascade involvingTNF-α [39, 40]. In addition to stimulating osteoclast activation through osteocyticapoptotic signaling, disuse may also induce osteoblast apoptosis, reducing thepopulation of bone forming cells. With fewer osteoblasts, the bone cannot be reformedas efficiently, leading to an uncoupling of resorption and formation. Before thoroughlydiscussing the roles of osteocyte and osteoblast apoptosis in disuse-induced bone loss,it is necessary to review some key apoptosis regulatory pathways in this family of cells.1.4.1 Review of apoptosis mechanisms in osteoblastsApoptosis is a form of genetically programmed cellular suicide in which damagedor unneeded cells are removed from tissue, as reviewed recently [41]. The apoptoticcascade is mediated by the activation of zymogens from the caspase family of cysteineproteases. Caspase activity is closely regulated by the B-cell/Lymphoma-2 (Bcl-2) familyof proteins including pro-apoptotic BAX and BAD; as well as anti-apoptotic Bcl-XL andBcl-2. In the osteoblast, apoptosis can occur through two different pathways (Figure1.1). The intrinsic pathway is initiated by damage to the DNA or an organelle. Followingsuch damage, the transcription factor p53 is activated—resulting in a halt in the G1phase of the cell cycle, which allows time for the cell to repair itself. If repair isunsuccessful, p53 up-regulates gene expression of BAX and down-regulates Bcl-2 [41].BAX mediates the release of cytochrome C from the mitochondria by permeabilizing themitochondrial membrane and releasing cytochrome C monomers. These monomersthen bind apoptosis protease activating factor-1 (Apaf-1) and caspase-9 monomersforming a gigantic (~1MDa) oligomeric complex called an apoptosome, or “the wheel ofdeath” [42]. This complex activates effector caspases by zymogen cleavage. Theextrinsic pathway involves stimulation of a death receptor (or perhaps, in the case ofdisuse, lack of stimulation of a mechanosensory receptor). Stimulation of the deathreceptor results in activation of caspase-8 which then activates effector caspases-3 and-7. Separately, caspase-8 also interacts with the intrinsic pathway by indirectly activating4