Ivabradine abrogates TNF-α-induced degradation of articular cartilage matrix.

Ivabradine is most commonly used for the treatment of worsening cardiac failure in patients who cannot tolerate the maximum dose of ß-blockers or in whom treatment with ß-blockers is contraindicated. While ivabradine is regarded as a highly selective "funny current" (If) inhibitor, the molecular mechanism behind the effect of this drug remains poorly understood. In the present study, we applied ivabradine in the context of osteoarthritis by treating primary human chondrocytes with tumor necrosis factor-α (TNF-α) and measuring degradation of the articular cartilage matrix as well as the expression of various enzymes and pro-inflammatory cytokines. Our results indicate that ivabradine significantly abrogated TNF-α-induced up-regulation of matrix metalloproteinase-3 (MMP-3), MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5 at both the gene and protein levels. Notably, ivabradine attenuated TNF-α-induced reduction of type II collagen and aggrecan at both the mRNA and protein levels. Also, we found that ivabradine inhibited the expression and secretion of interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) as well as the production of reactive oxygen species (ROS). Mechanistically, our results indicate that ivabradine abolished the activation of nuclear factor (NF-κB) by inhibiting nuclear translocation of NF-κB p65. Knockdown of HCN2 enhanced the protective effects of ivabradine against TNF-α- induced degradation of both type II collagen and aggrecan, suggesting that the inhibitory effects of ivabradine in ECM degradation might be mediated by HCN2. Our findings demonstrate that ivabradine may indeed have a potential application in preventing excessive degradation of the articular cartilage matrix, thereby preventing the pathological development and progression of osteoarthritis.

Retrospective analysis of the radiographic indicators for peri-acetabular osteotomy of developmental dysplasia in children.

PURPOSE: Open surgery, nonsurgical positioning device and casting are mainstay treatments of developmental dysplasia of the hip (DDH). The optimal indicators for surgical interventions remain unclear. In this study, we aim to establish empirical, sensitive radiographic indicators for peri-acetabular osteotomy intervention in developmental dysplasia in Chinese children. METHODS: One hundred and three DDH patients treated in The Soochow University Children's Hospital between 2006 and 2012 were assessed; patients with known causes of neuron muscular and abnormal hip joint origin were excluded. Fifty-four suitable patients, demonstrating 71 dysplasia hips with complete clinical record and adequate X-ray films, were enrolled in this study. Patients were divided into group A (conservative interventions failed, followed by salvage peri-acetabular osteotomy) and group B (conservative treatment only); a total of 16 quantitative parameters were measured on each pelvic X-ray film. RESULTS: Among 71 hip joints measured, 29 hips of group A underwent salvage peri-acetabular osteotomy (40.8 %,) showed higher X2, Y, h, and Smith c/b (Vh) (p < 0.05). The age, c, HT, b, A2 in the group A salvage operation were statistically significantly different compared to group B patients (without salvage operations) (p < 0.05). CONCLUSIONS: Pre-operative pelvic X-ray film assessment of acetabulum lateralization markers (X2, c, HT, c/b ratio) and the superior migration measurements (Y, h, h/b ratio) are potentially valuable radiographic indicators for determining which DDH patients will require peri-acetabular osteotomy.

P53 dependent mitochondrial permeability transition pore opening is required for dexamethasone-induced death of osteoblasts.

Prolonged or overdose glucocorticoids (GCs) usage is the common cause of osteoporosis. In the present study, we studied the cellular mechanism of dexamethasone (Dex)-induce osteoblast cell death by focusing on the role of mitochondrial permeability transition pore (mPTP). In cultured osteoblastic MC3T3-E1 cells, Dex-induced mPTP opening, which was demonstrated by mitochondrial membrane potential (MPP) decrease, cyclophilin-D (CyPD)-adenine nucleotide translocator 1 (ANT-1) mitochondrial complexation and cytochrome C (cyto-C) release. The mPTP inhibitor sanglifehrin A (SfA) dramatically inhibited Dex-induced MPP loss, cyto-C release and MC3T3-E1 cell death. Dex-induced cell death requires mPTP composing protein CyPD, as CyPD inhibitor cyclosporin A (CsA) and CyPD siRNA knockdown inhibited Dex-induced MC3T3-E1 cell death, while CyPD overexpression aggravated Dex's cytotoxic effect. We found that Dex induced P53 phosphorylation and translocation to mitochondria, where it formed a complex with CyPD. Glucocorticoid receptor (GR) siRNA knockdown, or P53 inhibition (by its inhibitor pifithrin-α or shRNA silencing) suppressed Dex-induced CyPD-P53 mitochondrial association and subsequent MC3T3-E1 cell death. Finally, in primary cultured osteoblasts, Dex-induced cell death was inhibited by CsA, SfA or pifithrin-α. Together, our data suggest that Dex-induced osteoblast cell death is associated with GR-P53-regulated mPTP opening.