Sumner, D.R.

Calcineurin/nuclear factor of activated T cells (NFAT) signaling in cobalt-chromium-molybdenum (CoCrMo) particles-induced tumor necrosis factor-α (TNFα) secretion in MLO-Y4 osteocytes (Article)

2011-05-10T00:00:00Z

Aseptic loosening is the devastating long term complication of total hip arthroplasty and orthopedic implant debris has been shown to trigger an intense inflammatory reaction leading to resorption of the bone matrix. Inflammatory cytokines, such as tumor necrosis factor-α (TNFα), have been implicated in this process and osteocytes may play a role in its production. We previously demonstrated that cobalt-chromium-molybdenum (CoCrMo) particles upregulate TNFα production by MLO-Y4 osteocytes in vitro, but the underlying mechanism has not been elucidated. Based on previous studies by others, we hypothesized that the calcineurin-nuclear factor of activated T cells (NFAT) pathway mediates CoCrMo particle-induced TNFα production in MLO-Y4 osteocytes. MLO-Y4 osteocytes exposed to CoCrMo particle treatment resulted in a rapid and significant increase in calcineurin activity. We also demonstrate that CoCrMo particle-induced upregulation of TNFα is reduced to control levels with calcineurin-NFAT inhibitors and this was also confirmed at mRNA level. Moreover, we demonstrate the localization of NFATs in MLO-Y4 osteocytes and that NFAT1 and 2 translocate to the nucleus upon CoCrMo particle treatment. Our results suggest that calcineurin-NFAT signaling is involved in TNFα production by MLO-Y4 osteocytes after CoCrMo particle treatment. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res Copyright

Bisphosphonate treatment affects trabecular bone apparent modulus through micro-architecture rather than matrix properties (Article)

2004-05-01T00:00:00Z

Bisphosphonates are emerging as an important treatment for osteoporosis. But whether the reduced fracture risk associated with bisphosphonate treatment is due to increased bone mass, improved trabecular architecture and/or increased secondary mineralization of the calcified matrix remains unclear. We examined the effects of bisphosphonates on both the trabecular architecture and matrix properties of canine trabecular bone. Thirty-six beagles were divided into a control group and two treatment groups, one receiving risedronate and the other alendronate at 5-6 times the clinical dose for osteoporosis treatment. After one year, the dogs were killed, and samples from the first lumbar vertebrae were examined using a combination of micro-computed tomography, finite element modeling, and mechanical testing. By combining these methods, we examined the treatment effects on the calcified matrix and trabecular architecture independently. Conventional histomorphometry and microdamage data were obtained from the second and third lumbar vertebrae of the same dogs [Bone 28 (2001) 524]. Bisphosphonate treatment resulted in an increased apparent Young's modulus, decreased bone turnover, increased calcified matrix density, and increased microdamage. We could not detect any change in the effective Young's modulus of the calcified matrix in the bisphosphonate treated groups. The observed increase in apparent Young's modulus was due to increased bone mass and altered trabecular architecture rather than changes in the calcified matrix modulus. We hypothesize that the expected increase in the Young's modulus of the calcified matrix due to the increased calcified matrix density was counteracted by the accumulation of microdamage.

Adaptation of subchondral bone in osteoarthritis (Article)

2004-01-01T00:00:00Z

Osteoarthritis is a chronic joint disease with pathological changes in the articulating cartilage and all other tissues that occupy the joint. Radin and coworkers have suggested the involvement of subchondral bone in the disease process. However, evidence for an essential role in the etiology has never been proven. Recent studies showing reduced chemical and mechanical properties of subchondral bone in various stages of the disease have invigorated interest in the role of subchondral bone in the development and progression of the disease. The current study showed that the concept of bone adaptation might explain subchondral stiffening, a process where subchondral bone becomes typically sclerotic in osteoarthritis. In addition, we report reduced mechanical matrix tissue properties as well as an increase in denatured collagen content. In conclusion, although osteoarthritic bone tissue contains increased denatured collagen and has reduced matrix mechanical properties, the widely accepted concept of subchondral stiffening is compatible with the process of normal bone adaptation.

Canine cancellous bone microarchitecture after one year of high-dose bisphosphonates (Article)

2003-04-03T00:00:00Z

We examined the effects of one-year high-dose bisphosphonates (risedronate 0.5 mg/kg/day or alendronate 1.0 mg/kg/day) on the three-dimensional (3-D) microstructural and mechanical properties of canine cancellous bone. A high-resolution micro-CT scanner was used to scan cubic specimens produced from the first lumbar vertebrae. Microstructural properties of the specimens were calculated directly from the 3-D datasets and the mechanical properties of the specimens were determined. Our data demonstrate significant microarchitectural changes in the bisphosphonate-treated cancellous bone that was typically plate-like, denser, with thicker and more trabeculae compared with those of the controls. Consistent with architectural changes, the Young's moduli of cancellous bone increased in all three directions with the greatest increase in primary axial loading (cephalo-caudal) direction after treatment. Our results suggest a bone remodeling-adaptation mechanism stimulated by bisphosphonates that increases bone volume fraction, thickens trabeculae, changes trabeculae towards more plate-like, and increases mechanical properties. The secondary degree of anisotropy contributed significantly to the explained variance in bone strength, and the primary or tertiary degree of anisotropy improved the explanation of variances for Young's moduli, i.e., 79% of strength variances or 74-83% of modulus variances could be explained by the combined anisotropy and bone volume fraction. These significant improvements of cancellous bone architecture provide a rationale for the clinical observation that fracture risk decreased by 50% in the first year of bisphosphonate therapy with only a 5% increase in bone mineral density. We conclude that bisphosphonates enhance mechanical properties and reduce fracture risk by improving architectural anisotropy of cancellous bone 3-D microarchitecture.

A decreased subchondral trabecular bone tissue elastic modulus is associated with pre-arthritic cartilage damage (Article)

2001-09-11T00:00:00Z

In osteoarthritis, one postulate is that changes in the mechanical properties of the subchondral bone layer result in cartilage damage. The goal of this study was to examine changes in subchondral trabecular bone properties at the calcified tissue level in the early stages of cartilage damage. Finite element models were constructed from microCT scans of trabectilar bone from the proximal tibia of donors with mild cartilage damage and from normal donors. In the donors with cartilage damage, macroscopic damage was present only in the medial compartment. The effective tissue elastic moduli were determined using a combination of finite element models and mechanical testing. The bone tissue modulus was reduced by 60% in the medial condyle of the cases with cartilage damage compared to the control specimens. Neither the presence of cartilage damage nor the anatomic site (medial vs. lateral) affected the elastic modulus at the apparent level. The volume fraction of trabecular bone was higher in the medial compartment compared to the lateral compartment of tibiae with cartilage damage (but not the controls), suggesting that mechanical properties were preserved in part at the apparent level by an increase in the bone volume fraction. It seems likely that the normal equilibrium between cartilage properties, bone tissue properties and bone volume fraction is disrupted early in the development of osteoarthritis.

Parallel plate model for trabecular bone exhibits volume fraction-dependent bias (Article)

2000-11-01T00:00:00Z

Unbiased stereological methods were used in conjunction with microcomputed tomographic (micro-CT) scans of human and animal bone to investigate errors created when the parallel plate model was used to calculate morphometric parameters. Bone samples were obtained from the human proximal tibia, canine distal femur, rat tail, and pig spine and scanned in a micro-CT scanner. Trabecular thickness, trabecular spacing, and trabecular number were calculated using the parallel plate model. Direct thickness, and spacing and connectivity density were calculated using unbiased three-dimensional methods. Both thickness and spacing calculated using the plate model were well correlated to the direct three-dimensional measures (r(2) = 0. 77-0.92). The correlation between trabecular number and connectivity density varied greatly (r(2) = 0.41-0.94). Whereas trabecular thickness was consistently underestimated using the plate model, trabecular spacing was underestimated at low volume fractions and overestimated at high volume fractions. Use of the plate model resulted in a volume-dependent bias in measures of thickness and spacing (p < 0.001). This was a result of the fact that samples of low volume fraction were much more "rod-like" than those of the higher volume fraction. Our findings indicate that the plate model provides biased results, especially when populations with different volume fractions are compared. Therefore, we recommend direct thickness measures when three-dimensional data sets are available.

Sensitivity of periprosthetic stress-shielding to load and the bone density-modulus relationship in subject-specific finite element models (Article)

2000-07-01T00:00:00Z

Subject-specific finite element (FE) computer models of the proximal femur in hip replacement could potentially predict stress-shielding and subsequent bone loss in individual patients. Before such predictions can be made, it is important first to determine if between subject differences in stress-shielding are sensitive to poorly defined parameters such as the load and the bone material properties. In this study we investigate if subject-specific FE models provide consistent stress-shielding patterns in the bone, independent of the choice of the loading conditions and the bone density-modulus relationship used in the computer model. FE models of two right canine femurs with and without implants were constructed based on contiguous computed tomography (CT) scans so that subject-specific estimates of stress-shielding could be calculated. Four different loading conditions and two bone density-modulus relationships were tested. Stress-shielding was defined as the decrease of strain energy per gram bone mass in the femur with the implant in place relative to the intact femur.The analyses showed that for the four loading conditions and two bone density-modulus relationships the difference in stress-shielding between the two subjects was essentially constant (1% variation) when the same loading condition and density-modulus relationship was used for both subjects. The severity of stress-shielding within a subject was sensitive to these input parameters, varying up to 20% in specific regions with a change in loading conditions and up to 10% for a change in the assumed density-modulus relationship. We conclude that although the choice of input parameters can substantially affect stress-shielding in an individual, this choice had virtually no effect on the relative differences in femoral periprosthetic stress-shielding between individuals. Thus, while care should be taken in the interpretation of the absolute value of stress-shielding calculated with these type of models, subject-specific FE models may be useful for explaining the variation in bone adaptation responsiveness between different subjects in experimental or clinical studies.

Nondestructive measurements of implant-bone interface shear modulus and effects of implant geometry in pull-out tests (Article)

1997-03-01T00:00:00Z

Push-out and pull-out tests are used for destructive evaluation of implant-bone interface strength. Because nondestructive mechanical tests would allow maintenance of an intact interface for subsequent morphological study, we developed such a test to determine the shear modulus of the interface by measuring the shear deformation of a thin layer adjacent to the implant. A polyurethane foam model was used to test the experimental setup on a group of nine cylindrical implants with three different lengths (15-48 mm) and three different diameters (5-9.7 mm). The shear modulus of the interface, as calculated from the pull-out test, was validated against the shear modulus of the foam derived from tensile tests. The two values of shear modulus were well correlated (R2 = 0.8, p < 0.001), thus encouraging further application of the setup for tests of implant-bone interface mechanics. In addition, we also examined the effects of implant length and diameter. The length of the implants had a significant influence on the interface shear modulus (p < 0.05), indicating that comparisons of the variable should only be made of implants with the same length. The length and diameter of the implants were not critical parameters for the ultimate fixation strength.