Abstract
Mechanical loading of bone is anabolic, while aseptic loosening of implants is catabolic. In a rat model of mechanically induced aseptic loosening, osteoclast differentiation is increased dramatically but the underlying mechanism is unknown. The objective was to profile molecular pathways in peri-implant bone resorption. Microarrays on cortical bone samples exposed to pressurized fluid flow were performed 3, 6, 12, 24 and 36 hrs, using time 0 as controls. Of a total of 4093 genes that underwent a 1.25-fold change (p<0.05) due to fluid flow only 21 were common for all time points. Signals linked to inflammation and apoptosis were regulated in a biphasic manner at 3 and 12 and/or 24 hrs. The acute response at 3 hrs was associated with increases in the cytokines IL-6, IL-11, LIF and STAT3. Levels of the pro-apoptotic factor TWEAK were higher while those of BOK, a second pro-survival molecule, were lower. There is an early and late rise in RIPK3, which stimulates a form of programmed necrosis. Osteoblast-related genes were clearly suppressed (osteocalcin, Col1a, PTHr1), while those regulating macrophage and osteoclast differentiation (CSF-1, Bach1, HO-1, RANKL, RANK, OPG) were enhanced. These data suggest that mechanical loading of cortical bone stimulates time-dependent expression of genes regulating the survival, necrosis and differentiation of both the myeloid and mesenchymal cell lineages, resulting in an integrated response leading to a rapid increase in osteoclast numbers.
