Right-tailed exact was used to analyze a value deciding the probability that all natural disease assigned

Besides the enhanced expression of genes coding for osteoclast stimulating ligands, e.g. VEGF, TGFB and CSF1, we also detected the osteoporosis-induced expression of Parathyroid hormone receptor PTH1R. Activation of PTH1R triggers osteoblast maturation and induces RANKL expression which leads to osteoclast precursor differentiation and activation. The enhanced expression of osteoclastogenesis promoting factors has already been described in fragility fractured bone and is in general consistent with the enhanced bone resorption described for osteoporosis. Because high age is one of the main risk factors for developing osteoporosis, we tried to dissect effects of aging from effects of primary LY2157299 osteoporosis by using hMSC from middle-aged donors as control cells for comparisons with hMSC-OP and hMSC-old, respectively, of elderly individuals. Surprisingly, the patterns of the differential gene expression in aged and osteoporotic hMSC differed widely. Only a few gene products with identical expression profiles in hMSC-old and hMSC-OP were observed and we therefore conclude that osteoporosis-associated changes are very distinct and independent of effects of clock-driven aging. We hypothesize that donors of advanced age who suffered from osteoarthritis but not from osteoporosis, aged in a healthier way than osteoporotic patients, or vice versa that osteoporosis is a distinct syndrome of premature aging. One hypothetical reason for aging is the loss of tissue regeneration due to replicative senescence of stem cells, which accumulates over time and ends in organ failure and death of the organism. Due to the fact that donors of hMSC-OP were of advanced age we analyzed whether these cells exhibited signs of replicative senescence by comparing them to the gene expression pattern of long term-cultivated, senescent hMSC. Thereby we detected a small overlap of genes differentially expressed in hMSC-OP and hMSC-senescent when compared to the identical control group hMSC-C. Despite the distinct gene expression pattern, we found some markers for replicative senescence in osteoporotic hMSC-OP, like the reduced expression of Hyaluronan receptor HMMR, which was described as inversely regulated to tumor suppressor P53, and the induction of CDKN1A, which codes for P21, another inhibitor of cyclindependent kinases. In contrast, analyses of nonosteoporotic hMSC-old of the age-matched donor group revealed no expression of markers for senescence and highlighted even more the differences between aging with and without primary osteoporosis. Our findings suggest that osteoporotic stem cells exhibit deficiencies in proliferation and might already be prone to a pre-senescent state. So far, reduction in proliferative activity in osteoporotic cells has only been described for osteoblasts. For confirmation, more detailed investigations of hMSC-OP on protein level and by proliferation or senescence studies are needed. In summary, this study indicates that intrinsic alterations in stem cell biology are involved in the pathophysiology of osteoporosis. By microarray analyses, we detected significant differences between hMSC of elderly donors with and without osteoporosis, suggesting that primary osteoporosis causes distinct transcriptional changes, which differ from age-related changes in non-osteoporotic donors. Next to indications for a pre-senescent state we detected enhanced transcription of inhibitors of WNT and BMP signaling in osteoporotic hMSC-OP, which can lead to functional deficiencies, such as autoinhibition of osteogenic differentiation and loss of selfrenewal. Our data facilitate the importance of well-known susceptibility genes of osteoporosis such as SOST, COL1A1 and LRP5, and additionally, we detected new candidate genes for further investigations, e.g. MAB21L2. Our study confirms that disturbed bone homeostasis by inhibition of osteogenic regeneration is at least an equally important feature of primary osteoporosis besides enhanced bone resorption. Therefore, ‘‘inhibition of inhibitors’’ of bone regeneration by using, e.g. SOST antibodies, is a mechanistically plausible treatment of the syndrome and will get even more attention in the future. Early-onset schizophrenia, that is, schizophrenia occurring prior to 17 years, affects approximately 1.6 to 1.9 per 100,000 of the child and adolescent population. It is a severe and debilitating disorder associated with considerable long-term impairments in psychological, social, educational and occupational functioning, poor physical health, reduced life expectancy, and substantial direct and indirect costs.

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