The Emerging Role of Osteocytes in Cancer in Bone

Advances in the last decade have established the osteocyte, the most abundant cell in bone, as a dynamic and multifunctional cell capable of controlling bone homeostasis by regulating the function of both osteoblasts and osteoclasts. In addition, accumulating evidence demonstrates that osteocyte function is altered in several skeletal disorders, and targeting osteocytes and their derived factors improves skeletal health. Despite the remarkable progress in our understanding of osteocyte biology, there has been a paucity of information regarding the role of osteocytes in the progression of cancer in bone. Exciting, recent discoveries suggest that tumor cells communicate with osteocytes to generate a microenvironment that supports the growth and survival of cancer cells and stimulates bone destruction. This review features these novel findings and discussions regarding the impact of chemotherapy on osteocyte function and the potential of targeting osteocytes for the treatment of cancer in bone. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research

Mechanobiological Principles Influence the Immune Response in Regeneration: Implications for Bone Healing

A misdirected or imbalanced local immune composition is often one of the reasons for unsuccessful regeneration resulting in scarring or fibrosis. Successful healing requires a balanced initiation and a timely down-regulation of the inflammation for the re-establishment of a biologically and mechanically homeostasis. While biomaterial-based approaches to control local immune responses are emerging as potential new treatment options, the extent to which biophysical material properties themselves play a role in modulating a local immune niche response has so far been considered only occasionally. The communication loop between extracellular matrix, non-hematopoietic cells, and immune cells seems to be specifically sensitive to mechanical cues and appears to play a role in the initiation and promotion of a local inflammatory setting. In this review, we focus on the crosstalk between ECM and its mechanical triggers and how they impact immune cells and non-hematopoietic cells and their crosstalk during tissue regeneration. We realized that especially mechanosensitive receptors such as TRPV4 and PIEZO1 and the mechanosensitive transcription factor YAP/TAZ are essential to regeneration in various organ settings. This indicates novel opportunities for therapeutic approaches to improve tissue regeneration, based on the immune-mechanical principles found in bone but also lung, heart, and skin

Alveolar epithelial and endothelial cell apoptosis in emphysema: What we know and what we need to know

Emphysema is mainly caused by cigarette smoking and is characterized by the loss of alveolar integrity and an enlargement of the alveolar space. However, mechanisms involved in its development are not fully understood. Alveolar cell apoptosis has been previously investigated in the lung of emphysematous subjects as a potential contributor to the loss of alveolar cell and has been found abnormally elevated. Though, mechanisms involved in the increased alveolar apoptosis that occurs in emphysema have now become a prolific field of research. Those mechanisms are reviewed here with special focus on how they affect cell viability and how they may be implicated in emphysema. Moreover, we suggest a model that integrates all those mechanisms to explain the increased alveolar apoptosis observed in emphysema. This review also includes some reflections and suggestions on the research to come

The bone marrow microenvironment – Home of the leukemic blasts

Acute Myeloid Leukaemia (AML) is a genetically, biologically and clinically heterogeneous set of diseases, which are characterised by an increased growth of abnormal myeloid progenitor cells within the bone marrow (BM). Ex-vivo AML exhibits a high level of spontaneous apoptosis. Furthermore, relapse for patients achieving remission occurs from minimal residual disease harboured within the BM microenvironment. Taken together, these observations illustrate the importance of the BM microenvironment in sustaining AML. While significant progress has been made elaborating the small-scale genetic mutations and larger-scale chromosomal translocations that contribute to the development of AML and its prognosis in response to treatment, less is understood about the complex microenvironment of the BM, which is known to be a key player in the pathogenesis of the disease. As we look towards future therapies, the consideration that the BM microenvironment is uniquely important as a niche for AML - coupled with the idea that leukaemic blasts are more likely to be genetically unstable and therefore evolve resistance to conventional chemotherapies - make the functions of the non-malignant cells of the BM attractive targets for therapy. In this review, we discuss the microanatomy of the BM and provide an overview of the evidence supporting the role of the BM microenvironment in creating conditions conducive to the survival and proliferation of AML blasts. Ultimately, we examine the therapeutic potential of uncoupling AML from the BM microenvironment

Consequences of Daily Administered Parathyroid Hormone on Myeloma Growth, Bone Disease, and Molecular Profiling of Whole Myelomatous Bone

Induction of osteolytic bone lesions in multiple myeloma is caused by an uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Current management of myeloma bone disease is limited to the use of antiresorptive agents such as bisphosphonates.We tested the effects of daily administered parathyroid hormone (PTH) on bone disease and myeloma growth, and we investigated molecular mechanisms by analyzing gene expression profiles of unique myeloma cell lines and primary myeloma cells engrafted in SCID-rab and SCID-hu mouse models. PTH resulted in increased bone mineral density of myelomatous bones and reduced tumor burden, which reflected the dependence of primary myeloma cells on the bone marrow microenvironment. Treatment with PTH also increased bone mineral density of uninvolved murine bones in myelomatous hosts and bone mineral density of implanted human bones in nonmyelomatous hosts. In myelomatous bone, PTH markedly increased the number of osteoblasts and bone-formation parameters, and the number of osteoclasts was unaffected or moderately reduced. Pretreatment with PTH before injecting myeloma cells increased bone mineral density of the implanted bone and delayed tumor progression. Human global gene expression profiling of myelomatous bones from SCID-hu mice treated with PTH or saline revealed activation of multiple distinct pathways involved in bone formation and coupling; involvement of Wnt signaling was prominent. Treatment with PTH also downregulated markers typically expressed by osteoclasts and myeloma cells, and altered expression of genes that control oxidative stress and inflammation. PTH receptors were not expressed by myeloma cells, and PTH had no effect on myeloma cell growth in vitro.We conclude that PTH-induced bone formation in myelomatous bones is mediated by activation of multiple signaling pathways involved in osteoblastogenesis and attenuated bone resorption and myeloma growth; mechanisms involve increased osteoblast production of anti-myeloma factors and minimized myeloma induction of inflammatory conditions

The Effects of Resveratrol on Oxidative Stress and Muscle Atrophy

Resveratrol (3,5,4,trihydroxystilbene) is a naturally occurring polyphenol found in over seventy plant species that has been shown to have anti-oxidant, anti-apoptotic and anti-aging properties. Resveratrols\u27 capacity to enhance the endogenous anti-oxidant system, upregulate anti-apoptotic proteins and improve mitochondrial function, presumably through the activation of the N AD+ dependent deacetylase Sirtuin1, suggests that supplementation with resveratrol may potentially protect skeletal muscle from the detrimental effects of increases in oxidative stress and the subsequent increase in apoptotic signaling that are present in many atrophic conditions. Therefore, the major goals of this dissertation are to further understand the interplay between oxidative stress and skeletal muscle atrophy and to evaluate the efficacy of resveratrol as a counter measure to both mitochondrial-induced oxidative stress and apoptosis.;The first study used hindlimb suspension (HLS) as a model of disuse atrophy as it is known to elicit muscle atrophy, oxidative stress and apoptosis in skeletal muscle. The aim of the investigation was to analyze the capacity of resveratrol administration at a moderate dose of 12.5mg/kg/day for 21 days to attenuate oxidative stress, apoptosis and muscle force loss following 14 days of HLS in young and aged rats. The study yielded mixed results. Resveratrol administration effectively reduced oxidative stress and subsequently oxidative damage in muscles from aged animals. Furthermore, resveratrol administration attenuated the relative loss of muscle mass as a ratio of animal body weight in gastrocnemius muscles from aged animals; however, despite reductions in apoptotic signaling in aged muscles, resveratrol administration was unable to mitigate apoptosis as measured by DNA fragmentation. Moreover, resveratrol administration had no protective effect on gastrocnemius muscles from young animals with regard to oxidative or apoptotic indices. Based on these results resveratrol has the potential to be an effective therapeutic agent to treat muscle functional decrements associated with disuse in aged individuals, via improving the redox status associated with these conditions.;The second half of the dissertation focuses on the capacity of long-term dietary supplementation with resveratrol to protect against aging-induced oxidative stress and to enhance mitochondrial signaling, and thus stem the progression of sarcopenia in aged skeletal muscle. In this study middle-aged (18mo) C57BL/6 mice were supplemented with a diet containing .05% trans-resveratrol for 10 months until they reached senescence (28mo). Gastrocnemius, plantaris and vastus lateralis muscles from supplemented animals were compared for anti-oxidant enzyme content and activities, oxidant load, oxidative damage, mitochondrial integrity and mass, as well as muscle function indices with muscles from young and middle-aged animals receiving a control diet. Resveratrol specifically upregulated the capacity of the mitochondrial isoform of superoxide dismutase (MnSOD) and concomitantly decreased hydrogen peroxide concentrations. This was paralleled by reductions in lipid peroxidation, but not protein oxidation in muscles from supplemented animals. Despite reductions in oxidant load and lipid peroxidation resveratrol, supplementation was unable to confer protection against sarcopenia. Furthermore, plantaris muscles from supplemented aged animals did not show enhanced resistance to muscle fatigue, nor an increase in maximal force production.;Taken as a whole these results suggest that resveratrol may be most effective when used as a pharmacological pre-conditioner to help confer resistance to oxidative damage under perturbations that are known to increase oxidative stress. Specifically, resveratrol may be an effective therapeutic agent to improve the redox status of aged skeletal muscle and therefore allow for improved adaptation and recovery following chronic illness and/or injuries during which the capacity of the endogenous antioxidant system may be overwhelmed in aged individuals. Gaining clearer insight into the molecular signaling pathways involved in aging and disuse muscle atrophy is paramount in developing nutritional and/or pharmacological interventions to minimize protein loss and attenuate the functional decrements associated with atrophic conditions. (Abstract shortened by UMI.)

Indonesian Journalist; After Political Reformation

For the first time ever, 385 professional journalists in Indonesia have been surveyed, by means of face-to-face interviews, for their basic characteristics and their views on professional values. The findings suggest that the ‘typical’ Indonesian journalist is young, male, well educated and earns an above-average salary. In terms of education and training, journalists of the archipelago are becoming increasingly professional. They see themselves as neutral and objective disseminators of news, though not as political actors and agents of development. Indonesian journalists disapprove of unscrupulous practices of reporting, yet many of them justify and practice corruption during their everyday work. Although the study’s primary focus is on Indonesia, the analysis goes well beyond national boundaries. By subjecting the data to factor analysis, five dimensions of media roles could be extracted, namely public-oriented news journalism, popular service journalism, critical watchdog journalism, objective precision journalism and opinion-oriented news journalism