SUMMARYChondrocyte differentiation is strictly regulated by various transcription factors, including Runx2 and Runx3; however, the physiological role of Runx1 in chondrocyte differentiation remains unknown. To examine the role of Runx1, we generated mesenchymal-cell-specific and chondrocyte-specific Runx1-deficient mice [Prx1 Runx1 f/f mice and a1(II) Runx1 f/f mice, respectively] to circumvent the embryonic lethality of Runx1-deficient mice. We then mated these mice with Runx2 mutant mice to obtain mesenchymal-cell-specific or chondrocyte-specific Runx1; Runx2 double-mutant mice [Prx1 DKO mice and a1(II) DKO mice, respectively]. Prx1 Runx1 f/f mice displayed a delay in sternal development and Prx1 DKO mice completely lacked a sternum. By contrast, a1(II) Runx1 f/f mice and a1(II) DKO mice did not show any abnormal sternal morphogenesis or chondrocyte differentiation. Notably, Runx1, Runx2 and the Prx1-Cre transgene were co-expressed specifically in the sternum, which explains the observation that the abnormalities were limited to the sternum. Histologically, mesenchymal cells condensed normally in the prospective sternum of Prx1 DKO mice; however, commitment to the chondrocyte lineage, which follows mesenchymal condensation, was significantly impaired. In situ hybridization analyses demonstrated that the expression of a1(II) collagen (Col2a1 -Mouse Genome Informatics), Sox5 and Sox6 in the prospective sternum of Prx1 DKO mice was severely attenuated, whereas Sox9 expression was unchanged. Molecular analyses revealed that Runx1 and Runx2 induce the expression of Sox5 and Sox6, which leads to the induction of a1(II) collagen expression via the direct regulation of promoter activity. Collectively, these results show that Runx1 and Runx2 cooperatively regulate sternal morphogenesis and the commitment of mesenchymal cells to become chondrocytes through the induction of Sox5 and Sox6.

Aseptic loosening is the most common cause of ortliopaedic implant failure. This process is thought to be due to osteolysis induced by implant-derived wear particles. Teitelbaum and colleagues have recently developed a promising murine calvarial model of wear particle-induced osteolysis. However, prior to this study, this model had only been assessed qualitatively. We now report a reproducible, quantitative version of the calvarial model of wear particle-induced osteolysis, in which the extent of osteolysis (and repair) of entire parietal bones is assessed by histomorphometry of contact microradiographs. Using this model, we found that the osteolytic response is transient and rapidly repaired in one month old mice. The extent of osteolysis peaks 7 days after particle implantation and returns to baseline levels by 13 days. A similar amount of osteolysis and even more extensive repair is observed when particles are implanted repeatedly. In contrast, aged mice develop progressive osteolysis with no detectable repair. As a result. 26 month old mice have approximately 17-fold more osteolysis than one month old mice 21 days after particle implantation.Skeletally mature, adult mice (4-16 months old) show an intermediate pattern of response. Osteolysis in these mice peaks at 7 days after particle implantation but it is repaired more slowly than in the one month old mice. Taken together, these results underscore the role of an imbalance between bone resorption and bone formation in the development of aseptic loosening and suggest that agents that stimulate bone formation maybe useful in prevention or treatment of aseptic loosening.

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The purpose of this study was to compare the osseointegration of surface-blasted Ti6A14V and CoCr implants in vivo. Ti6A14V and CoCr rods blasted with 710 microm A12O3 particles were bilaterally press-fit into the medullary space of distal femora of 24 rabbits. Evaluation was made radiographically, histologically, histomorphometrically (3, 6, and 12 weeks after implantation), and mechanically (12 weeks). Both Ti6A14V and CoCr implants demonstrated good biocompatibility radiographically and histologically. Toluidine blue-stained sections revealed an osteoconductive effect of the blasted surface, and fluorochrome labeling analysis showed active bone formation at the bone-implant interface at as late as 12 weeks for both specimens. CoCr showed significantly lower interfacial shear strength than Ti6A14V although the bone contact area with the implant surface was comparable and no intervening soft tissue at the bone-implant interface could be seen for either implant by scanning electron microscopy backscatter analysis. Unmineralized tissue (cartilage and osteoid) was observed more frequently on the CoCr surface than on the Ti6A14V surface. These data show less osseointegration of CoCr implants with this blasted surface for this short period, possibly due to a slight difference in surface roughness and some negative effects of CoCr on bone attachment.