BMD does not entirely explain an individual's risk of fracture. The purpose of this study was to assess whether specific differences in spatially resolved bone composition also contribute to fracture risk. These differences were assessed using Fourier transform infrared spectroscopic imaging (FTIRI) and analyzed through multiple logistic regression. Models were constructed to determine whether FTIRI measured parameters describing mineral content, mineral crystal size and perfection, and collagen maturity were associated with fracture. Cortical and cancellous bone were independently evaluated in iliac crest biopsies from 54 women (32 with fractures, 22 without) who had significantly different spine but not hip BMDs and ranged in age from 30 to 83 yr. The parameters that were significantly associated with fracture in the model were cortical and cancellous collagen maturity (increased with increased fracture risk), cortical mineral/ matrix ratio (higher with increased fracture risk), and cancellous crystallinity (increased with increased fracture risk). As expected, because of its correlation with cortical but not cancellous bone density, hip BMD was significantly associated with fracture risk in the cortical but not the cancellous model. This research suggests that additional parameters associated with fracture risk should be targeted for therapies for osteoporosis.
To gain insight into the effect of diabetes on fracture healing, experiments were carried out focusing on chondrocyte apoptosis during the transition from cartilage to bone. Type 1 diabetes was induced in mice by multiple low-dose streptozotocin injections, and simple transverse fractures of the tibia or femur was carried out. Large-scale transcriptional profiling and gene set enrichment analysis were performed to examine apoptotic pathways on total RNA isolated from fracture calluses on days 12, 16, and 22, a period of endochondral bone formation when cartilage is resorbed and chondrocyte numbers decrease. Tumor necrosis factor α (TNF-α) protein levels were assessed by ELISA and caspase-3 by bioactivity assay. The role of TNF was examined by treating mice with the TNF-specific inhibitor pegsunercept. In vitro studies investigated the proapoptotic transcription factor FOXO1 in regulating TNF-induced apoptosis of chondrogenic ATDC5 and C3H10T1/2 cells as representative of differentiated chondrocytes, which are important during endochondral ossification. mRNA profiling revealed an upregulation of gene sets related to apoptosis in the diabetic group on day 16 when cartilage resorption is active but not day 12 or day 22. This coincided with elevated TNF-α protein levels, chondrocyte apoptosis, enhanced caspase-3 activity, and increased FOXO1 nuclear translocation (p < .05). Inhibition of TNF significantly reduced these parameters in the diabetic mice but not in normoglycemic control mice (p < .05). Silencing FOXO1 using siRNA in vitro significantly reduced TNF-induced apoptosis and caspase activity in differentiated chondrocytes. The mRNA levels of the proapoptotic genes caspase-3, caspase-8, caspase-9, and TRAIL were significantly reduced with silencing of FOXO1 in chondrocytic cells. Inhibiting caspase-8 and caspase-9 significantly reduced TNF-induced apoptosis in chondrogenic cells. These results suggest that diabetes causes an upregulation of proapoptotic genes during the transition from cartilage to bone in fracture healing. Diabetes increased chondrocyte apoptosis through a mechanism that involved enhanced production of TNF-α, which stimulates chondrocyte apoptosis and upregulates mRNA levels of apoptotic genes through FOXO1 activation. © 2010 American Society for Bone and Mineral Research.
The polyunsaturated ω-3 fatty acid EPA-derived resolvin E1 (RvE1) enhances resolution of inflammation, prevents bone loss and induces bone regeneration. While the inflammation-resolving actions of RvE1 are characterized, molecular mechanism of its bone-protective actions are of interest. To test the hypothesis that receptor-mediated events impact bone changes, we prepared transgenic mice over expressing the RvE1 receptor chemR23 on leukocytes. In zymosan-initiated peritonitis, neutrophil polymorphonuclear leukocyte infiltration in response to RvE1 was limited requiring log order lower doses in chemR23tg mice. Ligature-induced alveolar bone loss was diminished in chemR23tg mice. Local RvE1 treatment of uniform craniotomy in the parietal bone significantly accelerated regeneration of the bone defect. In in vitro bone cultures, RvE1 significantly enhanced expression of osteoprotegerin (OPG) without inducing change in RANKL levels, while the osteogenic markers alkaline phosphatase, bone sialoprotein and Runt-related transcription factor 2 (RunX2) remained unchanged. These results indicate that RvE1 modulates osteoclast differentiation and bone remodeling by direct actions on bone, rescuing OPG production and restoring a favorable RANKL/OPG ratio, in addition to known anti-inflammatory and pro-resolving actions.
Bone mineral composition, crystallinity, and bone mineral content of osteoporotic patients are different from those of normal subjects. We review the evidence that these mineralization parameters contribute to the strength (fracture resistance) of bone and the methods that have been used to examine them. A specific example is provided from analysis of biopsies from the Multiple Outcomes in Raloxifene Evaluation trial. For the analyses, randomly selected biopsies from placebo, low-dose, and high-dose groups (n = 5 per group) obtained at time zero and 2 years after treatment were examined by infrared imaging spectroscopy. In all cases, comparable increases in mineral content were found, but there were no significant variations in mineral crystallinity.Osteoporosis is a devastating disease that affects more than 10 million people in the United States, with annual costs in excess of 13.5 billion dollars. 123 According to the US Surgeon General's Report, 123 by the year 2020 1/2 of all Americans older than 50 years will be at risk of an osteoporotic fragility fracture. Osteoporosis is characterized by low bone mass and structural deterioration of bone, leading to bone fragility and an increased tendency to fracture. Fracture resistance is determined by the strength of the bone, which in turn depends on its geometric properties (size, shape, and connectivity), the activities of the cells in the tissue, and the material properties of the tissue. 36,73,109 The material properties of bone include the mineral content, 73 mineral composition and mineral crystal size, 27 and matrix content and composition. 35 The most frequently used clinical indication of osteoporosis and fracture risk, bone mineral density (BMD), is also the most readily accessible non-invasive measure of bone mineral content. 85 The purpose of this review is to describe the additional properties that may be predictive of mechanical strength obtained by analyses of bone tissue specimens. Methods of analysis and recent data obtained by these methods also are reviewed to show how material properties are altered in osteoporosis.Specific questions addressed are how the composition of bone is altered in osteoporosis; how mineral crystal composition and size vary in osteoporosis; how spectroscopic analyses can be used to characterize these alterations in properties with high spatial resolution; and how therapies currently in clinical use affect these properties. The Composition of BoneBone is a composite consisting, in decreasing order, of mineral (an analogue of geologic hydroxyapatite [HA]), an organic matrix, cells, and water. 14 The organic matrix predominately Correspondence to:
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