MMP-13 stimulates osteoclast differentiation and activation in tumour breast bone metastases

INTRODUCTION: The increased bone degradation in osteolytic metastases depends on stimulation of mature osteoclasts and on continuous differentiation of new pre-osteoclasts. Metalloproteinases (MMP)-13 is expressed in a broad range of primary malignant tumours and it is emerging as a novel biomarker. Recent data suggest a direct role of MMP-13 in dissolving bone matrix complementing the activity of MMP-9 and other enzymes. Tumour-microenvironment interactions alter gene expression in malignant breast tumour cells promoting osteolytic bone metastasis. Gene expression profiles revealed that MMP-13 was among the up-regulated genes in tumour-bone interface and its abrogation reduced bone erosion. The precise mechanism remained not fully understood. Our purpose was to further investigate the mechanistic role of MMP-13 in bone osteolytic lesions. METHODS: MDA-MB-231 breast cancer cells that express MMP-13 were used as a model for in vitro and in vivo experiments. Conditioned media from MDA-MB-231 cells were added to peripheral blood mononuclear cultures to monitor pre-osteoclast differentiation and activation. Bone erosion was evaluated after injection of MMP-13-silenced MDA-MB-231 cells into nude mice femurs. RESULTS: MMP-13 was co-expressed by human breast tumour bone metastases with its activator MT1-MMP. MMP-13 was up-regulated in breast cancer cells after in vitro stimulation with IL-8 and was responsible for increased bone resorption and osteoclastogenesis, both of which were reduced by MMP inhibitors. We hypothesized that MMP-13 might be directly involved in the loop promoting pre-osteoclast differentiation and activity. We obtained further evidence for a direct role of MMP-13 in bone metastasis by a silencing approach: conditioned media from MDA-MB-231 after MMP-13 abrogation or co-cultivation of silenced cells with pre-osteoclast were unable to increase pre-osteoclast differentiation and resorption activity. MMP-13 activated pre-MMP-9 and promoted the cleavage of galectin-3, a suppressor of osteoclastogenesis, thus contributing to pre-osteoclast differentiation. Accordingly, MMP-13 abrogation in tumour cells injected into the femurs of nude mice reduced the differentiation of TRAP positive cells in bone marrow and within the tumour mass as well as bone erosion. CONCLUSIONS: These results indicate that within the inflammatory bone microenvironment MMP-13 production was up-regulated in breast tumour cells leading to increased pre-osteoclast differentiation and their subsequent activation

Non-epileptic myoclonus and mitochondrial encephalomyopathy

Two brothers presented to us with a progressive myoclonic syndrome with slight cerebellar symptoms. Neurological examination disclosed moderate cerebellar signs and pale optic discs; asymmetric, asynchronous and arhythmic myoclonus, an arthresthesic deficit and no muscular weakness. EEG background activity was moderately slow with no irritative discharges. CT was normal in both cases, Intermitent photic stimulation increased the frequency of the myoclonic jerks, which became bilateral and synchronous, progressing to a generalized tonic-clonic seizure. EPs and MRI in one case were normal. Anticonvulsant drugs were ineffective. The diagnosis of mitochondrial encephalomyopathy was based on the finding, in muscle specimens, of thickened basement membranes with myofibrillary degeneration and increased number of mitochondria peripherally distributed and with a dense granular matrix and some vacuoles. The clinical and EEG data suggest a. subcortical origin for this type of myoclonic syndrome

Embeddedness and locational choices: A study of creative workers in a dance organisation

Locational choices of creative workers have been a matter of heated debate over the last decade. This study proposes a micro perspective aimed at disentangling how the individual decision-making process behind locational choices is activated and develops over time. To this aim, we combine previous geographic research on the issue with research on the role of organisational factors in workers\u2019 attraction and retention. Empirically, we carried out an exploratory case study of dancers in a renowned contemporary ballet company based in Reggio Emilia, Italy. With this study, we high- light how matching professional quests and organisation-specific job opportunities activates loca- tional choices, and we extend geographical approaches to embeddedness by considering the role of organisations as crucial mediating entities between the city context and creative workers

Mental deterioration in lafora's disease

Lafora's disease is included among the progressive myoclonic epilepsies. Despite the fact that dementia is a constant finding in this disease only a few papers have studied the timing of riental deterioration. We have performed wide neuropsychological testing in two cases early diagnosed as Lafora disease. The initial neuropsychological testing was carried out by the time there were no complaints of mental deterioration in both cases. In the first case consecutive neuropsychological testing demonstrated the rapidly progressive dementia. All neuropsychological testings in these cases showed severe impairment of right parietal lobe functions. Higher cortical functions related to language and intelectual processes were beet preserved in both cases. The functions related to constructional praxis, memory and abstract concepts and processes were severily impaired. Our data suggest that mental deterioration is an early manifestation in Lafora disease, even by the time normal social life is not yet disturbed. Dominant hemisphere cognitivo functions have been less impaired than the non-dominant ones. How a diffuse illness such as Lafora disease can cause such an asymmetrical higher cortical function deficit is not yet clear