Periosteum: biology, regulation, and response to osteoporosis therapies

Periosteum contains osteogenic cells that regulate the outer shape of bone and work in coordination with inner cortical endosteum to regulate cortical thickness and the size and position of a bone in space. Induction of periosteal expansion, especially at sites such as the lumbar spine and femoral neck, reduces fracture risk by modifying bone dimensions to increase bone strength. The cell and molecular mechanisms that selectively and specifically activate periosteal expansion, as well as the mechanisms by which osteoporosis drugs regulate periosteum, remain poorly understood. We speculate that an alternate strategy to protect human bones from fracture may be through targeting of the periosteum, either using current or novel agents. In this review, we highlight current concepts of periosteal cell biology, including their apparent differences from endosteal osteogenic cells, discuss the limited data regarding how the periosteal surface is regulated by currently approved osteoporosis drugs, and suggest one potential means through which targeting periosteum may be achieved. Improving our understanding of mechanisms controlling periosteal expansion will likely provide insights necessary to enhance current and develop novel interventions to further reduce the risk of osteoporotic fractures

Lovastatin enhances adenovirus-mediated TRAIL induced apoptosis by depleting cholesterol of lipid rafts and affecting CAR and death receptor expression of prostate cancer cells

Oncolytic adenovirus and apoptosis inducer TRAIL are promising cancer therapies. Their antitumor efficacy, when used as single agents, is limited. Oncolytic adenoviruses have low infection activity, and cancer cells develop resistance to TRAIL-induced apoptosis. Here, we explored combining prostate-restricted replication competent adenovirus-mediated TRAIL (PRRA-TRAIL) with lovastatin, a commonly used cholesterol-lowering drug, as a potential therapy for advanced prostate cancer (PCa). Lovastatin significantly enhanced the efficacy of PRRA-TRAIL by promoting the in vivo tumor suppression, and the in vitro cell killing and apoptosis induction, via integration of multiple molecular mechanisms. Lovastatin enhanced PRRA replication and virus-delivered transgene expression by increasing the expression levels of CAR and integrins, which are critical for adenovirus 5 binding and internalization. Lovastatin enhanced TRAIL-induced apoptosis by increasing death receptor DR4 expression. These multiple effects of lovastatin on CAR, integrins and DR4 expression were closely associated with cholesterol-depletion in lipid rafts. These studies, for the first time, show correlations between cholesterol/lipid rafts, oncolytic adenovirus infection efficiency and the antitumor efficacy of TRAIL at the cellular level. This work enhances our understanding of the molecular mechanisms that support use of lovastatin, in combination with PRRA-TRAIL, as a candidate strategy to treat human refractory prostate cancer in the future

IGF-I improved bone mineral density and body composition of weaver mutant mice

Our recent report on a parallel decrease in the body weights and serum IGF-I levels of weaver mice suggests that IGF-I’s endocrine function may be impaired in neurodegenerative diseases. To further understand the overall effects of IGF-I deficiency on the postnatal growth, we measured bone mineral density (BMD), bone mineral content (BMC), lean body mass (LBM) and fat mass in male and female weaver mice and wild-type littermates on D21 (prepuberty), D45 (puberty), and D60 (postpuberty) using Dual-Energy X-ray Absorptionmetry (DEXA). In both male and female weaver mice, we found that the levels of circulating IGF-I paralleled those of BMD, BMC, and LBM, but not the fat mass. Male weaver mice have normal fat mass at all three ages studied, whereas female weaver mice showed a trend to increase their fat mass as they mature. To determine whether circulating IGF-I is a determinant of body composition, we crossbred IGF-I transgenic mice with homozygous weaver mice, which resulted in a significant increase in circulating IGF-I levels in both male and female weaver mice and normalization of their BMD, BMC and body weights. In summary, our results demonstrated that normal circulating IGF-I levels are important in maintaining BMD, BMC, and body composition in neurodegenerative diseases, such as hereditary cerebellar ataxia

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Novel interactions between FOXM1 and CDC25A regulate the cell cycle.

FOXM1 is a critical regulator of the G1/S and G2/M cell cycle transitions, as well as of the mitotic spindle assembly. Previous studies have suggested that FOXM1 regulates CDC25A gene transcription, but the mechanism remains unknown. Here, we provide evidence that FOXM1 directly regulates CDC25A gene transcription via direct promoter binding and indirect activation of E2F-dependent pathways. Prior literature reported that CDC25B and CDC25C activate CDK1/cyclinB complexes in order to enable phosphorylation of FOXM1. It was unknown if CDC25A functions in a similar manner. We report that FOXM1 transcriptional activity is synergistically enhanced when co-expressed with CDC25A. The increase is dependent upon CDK1 phosphorylation of FOXM1 at T600, T611 and T620 residues. We also report a novel protein interaction between FOXM1 and CDC25A via the C-terminus of FOXM1. We demonstrate that the phosphorylation of Thr 600 and Thr 611 residues of FOXM1 enhanced this interaction, and that the interaction is dependent upon CDC25A phosphatase activity. Our work provides novel insight into the underlying mechanisms by which FOXM1 controls the cell cycle through its association with CDC25A

Recql4 haploinsufficiency in mice leads to defects in osteoblast progenitors: Implications for low bone mass phenotype

The cellular and molecular mechanisms that underlie skeletal abnormalities in defective Recql4-related syndromes are poorly understood. Our objective in this study was to explore the function of Recql4 in osteoblast biology both in vitro and in vivo. Immunohistochemistry on adult mouse bone showed Recql4 protein localization in active osteoblasts around growth plate, but not in fully differentiated osteocytes. Consistent with this finding, Recql4 gene expression was high in proliferating mouse osteoblastic MC3T3.E1 cells and decreased as cells progressively lost their proliferation activity during differentiation. Recql4 overexpression in osteoblastic cells exhibited higher proliferation activity, while its depletion impeded cell growth. In addition, bone marrow stromal cells from male Recql4+/- mice had fewer progenitor cells, including osteoprogenitors, indicated by reduced total fibroblast colony forming units (CFU-f) and alkaline phosphatase-positive CFU-f colonies concomitant with reduced bone mass. These findings provide evidence that Recql4 functions as a regulatory protein during osteoprogenitor proliferation, a critical cellular event during skeleton development