No abstract

Activation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. Here we show that osteoclast dysfunction alone does not generally affect calcium homeostasis. Indeed, mice deficient in Src, encoding a tyrosine kinase critical for osteoclast activity, show signs of osteopetrosis, but without hypocalcemia or defects in bone mineralization. Mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells, have the expected defects in gastric acidification but also secondary hyperparathyroidism and osteoporosis and modest hypocalcemia. These results suggest that alterations in calcium homeostasis can be driven by defects in gastric acidification, especially given that calcium gluconate supplementation fully rescues the phenotype of the Cckbr-mutant mice. Finally, mice deficient in Tcirg1, encoding a subunit of the vacuolar proton pump specifically expressed in both osteoclasts and parietal cells, show hypocalcemia and osteopetrorickets. Although neither Src- nor Cckbr-deficient mice have this latter phenotype, the combined deficiency of both genes results in osteopetrorickets. Thus, we find that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification.

The InterTan device appears to be a reliable implant for the treatment of intertrochanteric femoral fractures. Its design provides for stability against rotation and minimizes neck malunions (shortening) through linear intraoperative compression of the head/neck segment to the shaft. As a result of the negligible complication rate and improved clinical outcomes, this implant is now the standard treatment for all intertrochanteric fractures at our institution.

No abstract

Fzd9, induced upon osteoblast differentiation, is required for bone matrix mineralization in primary osteoblasts.

These results indicate that estrogen seems to be an important factor in all stages of fracture healing. The application of estrogens enhances fracture healing of long bones at least in mice.

Fungal periprosthetic joint infection (PJI) is a rare but devastating complication following total knee arthroplasty (TKA). A standardized procedure regarding an accurate treatment of this serious complication of knee arthroplasty is lacking. In this systematic review, we collected data from 36 studies with a total of 45 reported cases of a TKA complicated by a fungal PJI. Subsequently, an analysis focusing on diagnostic, medicaments and surgical procedures in the pre-, intra- and postoperative period was performed. Candida spp. accounts for about 80% (36 out of 45 cases) of fungal PJIs and is therefore the most frequently reported pathogen. A systemic antifungal therapy was administered in all but one patient whereas a local antifungal therapy, e.g. the use of an impregnated spacer, is of inferior relevance. Resection arthroplasty with delayed re-implantation (two-stage revision) was the surgical treatment of choice. However, in 50% of all reported cases the surgical therapy was heterogeneous. The outcome under a combined therapy was moderate with recurrent fungal PJI in 11 patients and subsequent bacterial PJI as a main complication in 5 patients. In summary, this systematic review integrates data from up to date 45 reported cases of a fungal PJI of a TKA. On the basis of the current literature strategies for the treatment of this devastating complication after TKA are discussed.

Objective-3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert potent antiinflammatory effects that are independent of their cholesterol-lowering action. We have investigated the effects of these drugs on cytokine-stimulated CD40 expression in human cultured endothelial cells and monocytes. Methods and Results-Reverse transcription-polymerase chain reaction and Western blot analysis revealed that treatment of either cell type with atorvastatin, cerivastatin, or pravastatin (1 to 10 mol/L) inhibited interferon-␥ plus tumor necrosis factor-␣-stimulated CD40 expression by Ϸ50%, an effect that was not reversed by the HMG-CoA reductase product mevalonic acid (400 mol/L). In contrast, mevalonic acid prevented the inhibitory effect of atorvastatin on cytokine-stimulated vascular cell adhesion molecule-1 expression and subsequent adhesion of THP-1 monocytes to the cultured endothelial cells. Transcription factor analysis revealed an inhibition by atorvastatin of nuclear factor-B plus signal transducer and activator of transcription-1-dependent de novo synthesis of interferon regulatory factor-1, governing cytokine-stimulated CD40 expression in these cells. One consequence of this statin-dependent downregulation of CD40 expression was a decrease in CD40 ligand-induced endothelial interleukin-12 expression. A cell surface molecule, CD40 belongs to the family of tumor necrosis factor (TNF) receptors predominantly expressed by antigen-presenting cells but also by a variety of nonimmune cells. 1 In endothelial cells, CD40 stimulation via the corresponding ligand (CD40L) causes an increased expression of adhesion molecules and chemokines that promotes homing and extravasation of leukocytes at sites of inflammation. 2,3 Moreover, in response to CD40 stimulation, endothelial cells are capable of producing bioactive interleukin (IL)-12, 4 a potent differentiation factor for naive T helper cells that stimulates their clonal expansion into Th1 cells. 5 As a consequence, attenuation of CD40 expression and/or activity in endothelial cells appears to be a promising target for interfering with acute and chronic inflammatory responses, including atherosclerosis. Conclusions-ByConstitutive expression of CD40 in human endothelial cells is markedly enhanced on exposure to certain proinflammatory cytokines, namely, the combination of interferon (IFN)-␥ with TNF-␣. 6 Upregulation of CD40 expression under these conditions is mediated primarily by nuclear factor (NF)-B and signal transducer and activator of transcription (STAT)-1-dependent de novo synthesis of the transcription factor interferon regulatory factor (IRF)-1. 6 Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, collectively referred to as statins, exert therapeutic effects beyond lowering plasma cholesterol levels (see review 7 ). Thus, statins improve endothelial function through the upregulation of NO synthase expression, 8 they attenuate superoxide formation in these cells, 9 and they inhibit proinflammatory cytokine forma...