Bone can adapt its structure in response to mechanical stimuli. At the cellular level, this involves changes in chromatin organization, gene expression, and differentiation, but the underlying mechanisms are poorly understood. Here we report on the involvement of RUNX2, a bone-related transcription factor, in this process. Fluid flow shear stress loading of preosteoblasts stimulated translocation of extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) to the nucleus where it phosphorylated RUNX2 on the chromatin of target genes, and increased histone acetylation and gene expression. MAPK signaling and two RUNX2 phosphoacceptor sites, S301 and S319, were critical for this response. Similarly, in vivo loading of mouse ulnae dramatically increased ERK and RUNX2 phosphorylation as well as expression of osteoblast-related genes. These findings establish ERK/MAPK-mediated phosphorylation of RUNX2 as a critical step in the response of preosteoblasts to dynamic loading and define a novel mechanism to explain how mechanical signals induce gene expression in bone.

Recent clinical studies have linked failure to surgical variables of stemmed hip resurfacing systems. We used finite element analysis to investigate the effects of implant position, stem orientation, and extent of fixation both on the local stresses and strains associated with implant loosening, neck fracture, and stem fracture, as well as on the load transfer distribution in the bone-implant system. The range of peak stress in the cement was reduced from 11 to 13 MPa for the varus stem to 3.2 to 4.2 MPa for the valgus stem. The range of peak strain in the bone was also reduced from -0.35% to -0.45% strain for the varus stem to -0.19% to -0.27% strain for the valgus stem, but only when reamed cancellous bone remained exposed. Peak stresses in the stem were low for all cases. Additionally, the implant's load transfer distribution was generally insensitive to all variables examined and the femoral head was substantially unloaded. Our data indicate the local stresses and strains associated with implant loosening and neck fracture were reduced by placing the implant in a valgus orientation and covering reamed cancellous bone, but unloading of the femoral head, found for all variables examined, may lead to adverse bone remodeling.

Short-term femoral neck fracture is a primary complication associated with contemporary hip resurfacing. Some fractures are associated with neck notching, while others occur in the absence of notching. These unexplained fractures may be due to large magnitude strains near the implant rim, which could cause bone damage accumulation and eventual neck fracture. We used statistically augmented finite element analysis to identify design and environmental variables that increase bone strains near the implant rim after resurfacing, and lead to strain magnitudes sufficient for rapid damage accumulation. After resurfacing, the compressive strains in the inferior, peripheral neck increased by approximately 25%, particularly when the implant shell was bonded. While the tensile strains in the peripheral neck were low in magnitude in the immediate postoperative models, they increased substantially following compressive damage accumulation. Low bone modulus, within the range of normal bone, and high head load contributed the most to large magnitude strains. Therefore, in some cases, hip resurfacing may cause a region of compressive bone damage to develop rapidly, which in turn leads to large tensile strains and potential neck fracture. Our study suggests that indications for surgery should account for bone material quality, and that rehabilitation protocols should avoid high-load activities. ß

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