IGF2 derived from SH-SY5Y neuroblastoma cells induces the osteoclastogenesis of human monocytic precursors.

The insulin-like growth factors 2 (IGF2) is a peptide hormone that binds to the insulin-like growth factor 1 receptor (IGF1R) and is abundantly stored in bone. IGF1R is deeply involved in the pathogenesis of many cancers that growth within bone and is also involved in osteoclast biology. Among different cell lines representative of osteolytic tumors, we found a very high expression of IGF2 in SH-SY5Y cells derived from neuroblastoma (NB). We previously showed that NB cells induce an osteolytic process through the Osteoprotegerin/RANKL/RANK and the canonical Wnt pathway system. Here, we hypothesized that NB promotes osteoclastogenesis also via IGF2. First, we demonstrated the presence of IGF1R on the osteoclast basolateral membrane, and we observed a cyclic IGF1R activation along with the differentiation process, also when induced by SH-SY5Y. Moreover, we found that IGF2 mRNA expression in SH-SY5Y cells was further increased when co-cultured with mesenchymal stromal cells, suggesting that IGF2 is important for NB interaction with the bone microenvironment. Finally, the treatment of SH-SY5Y cells with an anti-IGF2 siRNA or the addition of anti-IGF1R molecules impaired NB-induced osteoclastogenesis, even though the chemoattraction of monocytes by NB cells was unaffected. Our findings suggest that in IGF2-producing osteolytic tumors IGF1R is a good candidate for targeted therapies in combination with conventional drugs.

Spousal concordance for major coronary risk factors: a systematic review and meta-analysis.

Spousal pairs permit assessment of determinants of diseases related to environment, because they share the same lifestyle and environment. The authors reviewed spouses' concordance for the major coronary risk factors. A search of the MEDLINE, PubMed, and EMBASE databases was performed. Seventy-one papers were selected for a total of 207 cohorts of pairs and 424,613 correlations in more than 100,000 couples. The most strongly correlated within-pairs factors were smoking and body mass index, with overall correlations of 0.23 (95% confidence interval: 0.12, 0.36) and 0.15 (95% confidence interval: 0.05, 0.25), respectively. Statistically significant positive correlations were also found for diastolic blood pressure, triglycerides, total and low density lipoprotein cholesterol, weight, and the waist/hip ratio. The overall odds ratios for concordance in hypertension, smoking, diabetes, and obesity were all statistically significant, ranging from 1.16 to 3.25. Assortative mating influenced concordance for blood pressure, smoking, glucose, low density lipoprotein cholesterol, weight, body mass index, and waist circumference. This systematic review shows a statistically significant positive spousal concordance for the majority of main coronary risk factors. However, the strength of the concordance was markedly different among factors and appeared to be quite modest for all of them. Interventions to reduce cardiovascular risk factors should be addressed jointly to both members of a marital couple.

Cardiovascular risk factors and global risk of fatal cardiovascular disease are positively correlated between partners of 802 married couples from different European countries. Report from the IMMIDIET project.

Shared environmental factors may confer to spouses a similar risk for cardiovascular disease. We aimed at investigating in pairs the concordance in risk factors for cardiovascular disease and in global risk of cardiovascular events. In the framework of the IMMIDIET Project, married couples, recruited randomly from general practice, were studied. One thousand six hundred and four apparently healthy subjects aged 25-74 years from three different European populations were enrolled. Individual cardiovascular risks were estimated using SCORE risk equations. Age was strongly correlated within couples (r = 0.86, P < 0.0001). In multivariate model, within-pair correlation was high for social status (r = 0.49; percentage of explained variation = 24%) and percent of calories from lipids (r = 0.34; 12%). Concerning conventional metabolic risk factors, percentage of explained variation varied from 0.5% (triglycerides) to 11% (glucose). Among new risk factors, activated factor VII showed the strongest correlation (r = 0.28) and C-reactive protein the lowest (r = 0.13). Either total, coronary or non-coronary risk estimates at 10 years were strongly correlated within pairs: the risk of a member explained about two thirds of the cardiovascular risk of the partner. Spouse pairs share common lifestyle habits, common and new metabolic risk factors and the predicted global risk of cardiovascular events. If the individual risk of a person is influenced by the risk of his/her partner, decreasing the risk in a member of the pair should also decrease the risk in the partner. These concepts may have important public health consequences in targeting screening or disease prevention measures towards partners of people with cardiovascular risk.

Effects of antisense mediated inhibition of cathepsin K on human osteoclasts obtained from peripheral blood.

Cathepsin K is a cystein protease that displays a proteolytic activity against Type I collagen and is abundantly and selectively expressed in osteoclasts where it plays a critical role in bone degradation. Its direct role in bone tissue has been defined by knock-out mice studies and inhibiting strategies in animals models. However, direct proof of cathepsin K function in human osteoclast model in vitro is lacking. The aim of this study is to analyze cathepsin K expression and localization in human osteoclasts obtained from peripheral blood and to examine cathepsin K function in these cells by antisense oligodeoxynucleotide (AS-ODN) strategy. AS-ODN was added to the culture of osteoclast precursors induced to differentiate by RANKL and M-CSF. AS-ODN treatment produced a significant down-regulation of cathepsin K mRNA (>80%) and protein expression, as verified respectively by Real-time PCR and by immunocytochemistry or Western blot. The cathepsin K inhibition caused an impairment of resorption activity as evaluated by a pit formation assay ( p = 0.045) and by electron microscopy, while the acidification process was unaffected. We demonstrated that antisense strategies against cathepsin K are selectively effective to inhibit resorption activity in human osteoclasts, like in animal models.