Bisphosphonate-related osteonecrosis of jaw (BRONJ): an anti-angiogenic side-effect?

Bisphosphonates are recommended in the treatment of osteoporosis and some cancers, in which case they prevent the appearance of bone metastasis. The patients taking bisphosphonates are at increased risk of developing bisphosphonate-related osteonecrosis of jaw (BRONJ) which is characterised by the presence of an un-healing wound after dental surgery. BRONJ might represent an anti-angiogenic side effect. However, the real number of patients with BRONJ might be higher than currently recorded. Considering the differential diagnosis which includes various primary and secondary cancers, a correct histopathological diagnosis is very important. The morphological criteria for diagnosis of BRONJ are highlighted in this material.Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1813972972323288. © 2012 Petcu et al.; licensee BioMed Central Ltd

Mesenchymal Stem Cells Loaded with p5, Derived from CDK5 Activator p35, Inhibit Calcium-Induced CDK5 Activation in Endothelial Cells.

The potential use of stem cells as therapeutics in disease has gained momentum over the last few years and recently phase-I clinical trials have shown favourable results in treatment of a small cohort of acute stroke patients. Similarly, they have been used in preclinical models drug-loaded for the effective treatment of solid tumours. Here we have characterized uptake and release of a novel p5-cyclin-dependent kinase 5 (CDK5) inhibitory peptide by mesenchymal stem cells and showed release levels capable of blocking aberrant cyclin-dependent kinase 5 (CDK5) signaling pathways, through phosphorylation of cyclin-dependent kinase 5 (CDK5) and p53. These pathways represent the major acute mechanism stimulating apoptosis after stroke and hence its modulation could benefit patient recovery. This work indicates a potential use for drug-loaded stem cells as delivery vehicles for stroke therapeutics and in addition as anticancer receptacles particularly, if a targeting and/or holding mechanism can be defined

Bisphosphonate-related osteonecrosis of jaw (BRONJ): diagnostic criteria and possible pathogenic mechanisms of an unexpected anti-angiogenic side effect.

Recently, bisphosphonates (BPs) have been widely used in medical practice as anti-resorptive agents owing to their anti-osteoclatic action. In addition, these compounds are also used for their analgesic action and their potential anti-tumour effect. Patients treated with BPs may subsequently develop osteonecrosis of the jaw or maxillary bone after minor local trauma including dental work, recently labelled as bisphosphonate osteonecrosis of jaw (BRONJ). However, the etiopathogenic mechanisms of this pathological condition are poorly understood. Although, several pathways have been proposed for BRONJ occurrence, no single model can explain all morphological changes observed at the macro- and microscopic level. Recent research suggests that BPs may promote an anti-angiogenic effect which contributes directly to the clinical features associated with BRONJ. Remarkably, the anti-angiogenic effect promoting BRONJ might be in keeping with the anti-neoplastic action of BPs. The current review, presents clinical diagnostic criteria. In addition, based on our own experience we describe the histopathological criteria for diagnosis of BRONJ and the possible pathways which may lead to this frustrating pathological condition

Citicoline induces angiogenesis improving survival of vascular/human brain microvessel endothelial cells through pathways involving ERK1/2 and insulin receptor substrate-1.

BACKGROUND: Citicoline is one of the neuroprotective agents that have been used as a therapy in stroke patients. There is limited published data describing the mechanisms through which it acts. METHODS: We used in vitro angiogenesis assays: migration, proliferation, differentiation into tube-like structures in Matrigel™ and spheroid development assays in human brain microvessel endothelial cells (hCMEC/D3). Western blotting was performed on protein extraction from hCMEC/D3 stimulated with citicoline. An analysis of citicoline signalling pathways was previously studied using a Kinexus phospho-protein screening array. A staurosporin/calcium ionophore-induced apoptosis assay was performed by seeding hCMEC/D3 on to glass coverslips in serum poor medium. In a pilot in vivo study, transient MCAO in rats was carried out with and without citicoline treatment (1000 mg/Kg) applied at the time of occlusion and subsequently every 3 days until euthanasia (21 days). Vascularity of the stroke-affected regions was examined by immunohistochemistry. RESULTS: Citicoline presented no mitogenic and chemotactic effects on hCMEC/D3; however, it significantly increased wound recovery, the formation of tube-like structures in Matrigel™ and enhanced spheroid development and sprouting. Citicoline induced the expression of phospho-extracellular-signal regulated kinase (ERK)-1/2. Kinexus assays showed an over-expression of insulin receptor substrate-1 (IRS-1). Knock-down of IRS-1 with targeted siRNA in our hCMEC/D3 inhibited the pro-angiogenic effects of citicoline. The percentage of surviving cells was higher in the presence of citicoline. Citicoline treatment significantly increased the numbers of new, active CD105-positive microvessels following MCAO. CONCLUSIONS: The findings demonstrate both a pro-angiogenic and protective effect of citicoline on hCMEC/D3 in vitro and following middle cerebral artery occlusion (MCAO) in vivo

Attenuated Inflammatory Response in Aged Mice Brains following Stroke

Background: Increased age is a major risk factor for stroke incidence, post-ischemic mortality, and severe and long-term disability. Stroke outcome is considerably influenced by post-ischemic mechanisms. We hypothesized that the inflammatory response following an ischemic injury is altered in aged organisms. Methods and Results: To that end, we analyzed the expression pattern of pro-inflammatory cytokines (TNF, IL-1a, IL-1b, IL-6), anti-inflammatory cytokines (IL-10, TGFb1), and chemokines (Mip-1a, MCP-1, RANTES) of adult (2 months) and aged (24 months) mice brains at different reperfusion times (6 h, 12 h, 24 h, 2 d, 7 d) following transient occlusion of the middle cerebral artery. The infarct size was assessed to monitor possible consequences of an altered inflammatory response in aged mice. Our data revealed an increased neuro-inflammation with age. Above all, we found profound age-related alterations in the reaction to stroke. The response of pro-inflammatory cytokines (TNF, and IL-1b) and the level of chemokines (Mip-1a, and MCP-1) were strongly diminished in the aged post-ischemic brain tissue. IL-6 showed the strongest age-dependent decrease in its post-ischemic expression profile. Anti-inflammatory cytokines (TGFb1, and IL-10) revealed no significant age dependency after ischemia. Aged mice brains tend to develop smaller infarcts. Conclusion: The attenuated inflammatory response to stroke in aged animals may contribute to their smaller infarcts. The results presented here highlight the importance of using aged animals to investigate age-associated diseases like stroke