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NASA NTRS2004

Cellular Mechanisms Underlying Bone-Forming Cell Proliferative Response to Hypergravity

Life on Earth has evolved under the continuous influence of gravity (1-g). As humans explore and develop space, however, we must learn to adapt to an environment with little or no gravity. Studies indicate that lack of weightbearing for vertebrates occurring with immobilization, paralysis, or in a microgravity environment may cause muscle and bone atrophy through cellular and subcellular level mechanisms. We hypothesize that gravity is needed for the efficient transduction of cell growth and survival signals from the extra-cellular matrix (ECM) (consisting of molecules such as collagen, fibronectin, and laminin) in mechanosensitive tissues. We test for the presence of gravity-sensitive pathways in bone-forming cells (osteoblasts) using hypergravity applied by a cell culture centrifuge. Stimulation of 50 times gravity (50-g) increased proliferation in primary rat osteoblasts for cells grown on collagen Type I and fibronectin, but not on laminin or uncoated surfaces. Survival was also enhanced during hypergravity stimulation by the presence of ECM. Bromodeoxyuridine incorporation in proliferating cells showed an increase in the number of actively dividing cells from about 60% at 1-g to over 90% at 25-g. Reverse transcription-polymerase chain reaction was used to test for all possible integrins. Our combined results indicate that beta1 and/or beta3 integrin subunits may be involved. These data indicate that gravity mechanostimulation of osteoblast proliferation involves specific matrix-integrin signalling pathways which are sensitive to g-level. Further research to define the mechanisms involved will provide direction so that we may better adapt and counteract bone atrophy caused by the lack of weightbearing.

Vercoutere, W.↗

NASA NTRS1993

Skeletal muscle satellite cells cultured in simulated microgravity

Satellite cells are postnatal myoblasts responsible for providing additional nuclei to growing or regenerating muscle cells. Satellite cells retain the capacity to proliferate and differentiate in vitro and therefore provide a useful model to study postnatal muscle development. Most culture systems used to study postnatal muscle development are limited by the two-dimensional (2-D) confines of the culture dish. Limiting proliferation and differentiation of satellite cells in 2-D could potentially limit cell-cell contacts important for developing the level of organization in skeletal muscle obtained in vivo. Culturing satellite cells on microcarrier beads suspended in the High-Aspect-Ratio-Vessel (HARV) designed by NASA provides a low shear, three-dimensional (3-D) environment to study muscle development. Primary cultures established from anterior tibialis muscles of growing rats (approximately 200 gm) were used for all studies and were composed of greater than 75 % satellite cells. Different inoculation densities did not affect the proliferative potential of satellite cells in the HARV. Plating efficiency, proliferation, and glucose utilization were compared between 2-D flat culture and 3-D HARV culture. Plating efficiency (cells attached - cells plated x 100) was similar between the two culture systems. Proliferation was reduced in HARV cultures and this reduction was apparent for both satellite cells and non-satellite cells. Furthermore, reduction in proliferation within the HARV could not be attributed to reduced substrate availability since glucose levels in media from HARV and 2-D cell culture were similar. Morphologically, microcarrier beads within the HARVS were joined together by cells into three-dimensional aggregates composed of greater than 10 beads/aggregate. Aggregation of beads did not occur in the absence of cells. Myotubes were often seen on individual beads or spanning the surface of two beads. In summary, proliferation and differentiation of satellite cells on microcarrier beads within the HARV bioreactor results in a three dimensional level of organization that could provide a more suitable model to study postnatal muscle development.

Molnar, Greg↗

NASA NTRS1992

Proliferation and performance of hybridoma cells in microgravity (7-IML-1)

The purpose of this experiment is to study how cell performance (biosynthesis and secretion) is altered by altered gravity conditions. Hybridoma cells are obtained by fusion of an activated B-lymphocyte with a myeloma cell. Activated B-lymphocytes, derived from a human or an animal, carry the information required to produce antibodies of a certain specificity and can survive only a few days in culture. Myeloma cells are tumor cells which can grow indefinitely in culture. Therefore, the product of the fusion is an immortal cell line capable of producing homogeneous antibodies (monoclonal antibodies). Experimental procedures are explained in some detail.

Cogoli, Augusto↗

NASA NTRS2003

Human Peripheral Blood Mononuclear Cells Cultured in Normal and Hyperglycemic Media in Simulated Microgravity Using NASA Bioreactors

We sought answers to several questions this summer at NASA Johnson Space Center. Initial studies involved the in vitro culture of human peripheral blood mononuclear in cells in different conditioned culture media. Several human cancer clones were similarly studied to determine responses to aberrant glycosylation by the argon laser. The cells were grown at unit gravity in flasks and in simulated microgravity using NASA bioreactors. The cells in each instance were analyzed by flow cytometry. Cell cycle analysis was acquired by staining nuclear DNA with propidium iodide. Responses to the laser stimulation was measured by observing autofluorescence emitted in the green and red spectra after stimulation. Extent of glycosylation correlated with the intensity of the laser stimulated auto-fluorescence. Our particular study was to detect and monitor aberrant glycosylation and its role in etiopathogenesis. Comparisons were made between cells known to be neoplastic and normal cell controls using the same Laser Induced Autofluorescence technique. Studies were begun after extensive literature searches on using the antigen presenting potential of dendritic cells to induce proliferation of antigen specific cytotoxic T-cells. The Sendai virus served as the antigen. Our goal is to generate sufficient numbers of such cells in the simulated microgravity environment for use in autologous transplants of virally infected individuals including those positive for hepatitis and HIV.

Lawless, DeSales↗

NASA NTRS1999

The Effects of Orbital Spaceflight on Human Osteoblastic Cell Physiology and Gene Expression

The purpose of the proposed study is to establish whether changes in gravitational loading have a direct effect on osteoblasts to regulate TGF-6 expression. The effects of spaceflight and reloading on TGF-B MRNA and peptide levels will be studied in a newly developed line of immortalized human fetal osteoblasts (HFOB) transfected with an SV-40 temperature dependent mutant to generate proliferating, undifferentiated hFOB cells at 33-34 C and a non-proliferating, differentiated HFOB cells at 37-39'C. Unlike previous cell culture models, HFOB cells have unlimited proliferative capacity yet can be precisely regulated to differentiate into mature cells which express mature osteoblast function. If isolated osteoblasts respond to changes in mechanical loading in a manner similar to their response in animals, the cell system could provide a powerful model to investigate the signal transduction pathway for gravitational loading.

Turner, R. T.↗

NASA NTRS2015

Transient Gene and miRNA Expression Profile Changes of Confluent Human Fibroblast Cells in Space

Microgravity or an altered gravity environment from the static 1 gravitational constant has been shown to influence global gene expression patterns and protein levels in cultured cells. However, most of the reported studies conducted in space or using simulated microgravity on the ground have focused on the growth or differentiation of the cells. Whether non-dividing cultured cells will sense the presence of microgravity in space has not been specifically addressed. In an experiment conducted on the International Space Station, confluent human fibroblast cells were fixed after being cultured in space for 3 and 14 days for investigations of gene and miRNA (microRNA) expression profile changes in these cells. A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for tissues, and plays a critical role in wound healing and other functions. Results of the experiment showed that on Day 3, both the flown and ground cells were still proliferating slowly even though they were confluent, as measured by the expression of the protein Ki-67 positive cells, and the cells in space grew slightly faster. Gene and miRNA expression data indicated activation of NF(sub kappa)B (nuclear factor kappa-light-chain-enhancer of activated B cells) and other growth related pathways involving HGF and VEGF in the flown cells. On Day 14 when the cells were mostly non-dividing, the gene and miRNA expression profiles between the flight and ground samples were indistinguishable. Comparison of gene and miRNA expressions in the Day 3 samples in respect to Day 14 revealed that most of the changes observed on Day 3 were related to cell growth for both the flown and ground cells. Analysis of cytoskeleton changes by immunohistochemistry staining of the cells with antibodies for alpha-tubulin showed no difference between the flight and ground samples. Results of our study suggest that in true non-dividing human fibroblast cells, microgravity in space has little effect on the gene and miRNA expression. Gene and miRNA expression changes were observed in cells that were confluent, but still proliferating slowly. The faster growth in the flown cells was associated with the activation of NF(sub kappa)B pathways which triggers the expression of several growth factors and the suppression of the cell cycle checkpoint.

Zhang, Ye↗

NASA NTRS2017

The Role of CDKN1a/p21 in Cellular Senescence of Bone Marrow Stem Cells Under Spaceflight Stressors

Spaceflight environments and their associated conditions, such as microgravity and space radiation, cause many biological functions formerly considered to be standard to behave in nonstandard ways. Exposure to microgravity has shown to induce deleterious effects in stem cell-based tissue regeneration, leading to immune system and healing response impairments as well as muscle and bone density loss. Such risks must be mitigated in order for long-term human space exploration to proceed. Thus, our work seeks to explore mechanisms of stem cell-based tissue regeneration that experience changes in spaceflight environments. Cellular senescence is a process of inducing cell cycle arrest that can be initiated by various stimuli. This function is influenced by two major pathways, controlled by p53 and pRB tumor suppressor proteins. p53 activity targets the cyclin-dependent kinase inhibitor gene p21Cdkn1a in osteogenic cell cycle arrest. Under conditions of mechanical unloading, stem cell-based tissue regeneration has shown to be decreased in both proliferation and differentiation, as many cells are arrested in progenitor states. p21 has shown upregulation in expression under conditions of microgravity, suggesting its role in regenerative bone formation arrest in space. p21 levels are found to be elevated independent of p53, suggesting a decrease in proliferation and regeneration without apoptosis, but rather through cell cycle arrest alone. Thus, we hypothesize that p21 is a mediator of cellular senescence in bone marrow stem cells. Culturing of bone marrow stem cells from wild type and p21 knockout mice under osteoblastogenic conditions will be completed to explore the role of p21Cdkn1a in stem cell proliferation and maturation. We believe that decreases in somatic stem cell differentiation may occur after spaceflight due to signal pathway alterations that result in downstream inhibition of genes involved in differentiation, preventing tissue from repairing and regenerating normally.

Stem Cells↗

NASA NTRS1997

Induction of cyclo-oxygenase-2 mRNA by prostaglandin E2 in human prostatic carcinoma cells

Prostaglandins are synthesized from arachidonic acid by the enzyme cyclo-oxygenase. There are two isoforms of cyclooxygenases: COX-1 (a constitutive form) and COX-2 (an inducible form). COX-2 has recently been categorized as an immediate-early gene and is associated with cellular growth and differentiation. The purpose of this study was to investigate the effects of exogenous dimethylprostaglandin E2 (dmPGE2) on prostate cancer cell growth. Results of these experiments demonstrate that administration of dmPGE2 to growing PC-3 cells significantly increased cellular proliferation (as measured by the cell number), total DNA content and endogenous PGE2 concentration. DmPGE2 also increased the steady-state mRNA levels of its own inducible synthesizing enzyme, COX-2, as well as cellular growth to levels similar to those seen with fetal calf serum and phorbol ester. The same results were observed in other human cancer cell types, such as the androgen-dependent LNCaP cells, breast cancer MDA-MB-134 cells and human colorectal carcinoma DiFi cells. In PC-3 cells, the dmPGE2 regulation of the COX-2 mRNA levels was both time dependent, with maximum stimulation seen 2 h after addition, and dose dependent on dmPGE2 concentration, with maximum stimulation seen at 5 microg ml(-1). The non-steroidal anti-inflammatory drug flurbiprofen (5 microM), in the presence of exogenous dmPGE2, inhibited the up-regulation of COX-2 mRNA and PC-3 cell growth. Taken together, these data suggest that PGE2 has a specific role in the maintenance of human cancer cell growth and that the activation of COX-2 expression depends primarily upon newly synthesized PGE2, perhaps resulting from changes in local cellular PGE2 concentrations.

Non-NASA Center↗

NASA NTRS1994

Calcium influences sensitivity to growth inhibition induced by a cell surface sialoglycopeptide

While studies concerning mitogenic factors have been an important area of research for many years, much less is understood about the mechanisms of action of cell surface growth inhibitors. We have purified an 18 kDa cell surface sialoglycopeptide growth inhibitor (CeReS-18) which can reversibly inhibit the proliferation of diverse cell types. The studies discussed in this article show that three mouse keratinocyte cell lines exhibit sixty-fold greater sensitivity than other fibroblasts and epithelial-like cells to CeReS-18-induced growth inhibition. Growth inhibition induced by CeReS-18 treatment is a reversible process, and the three mouse keratinocyte cell lines exhibited either single or multiple cell cycle arrest points, although a predominantly G0/G1 cell cycle arrest point was exhibited in Swiss 3T3 fibroblasts. The sensitivity of the mouse keratinocyte cell lines to CeReS-18-induced growth inhibition was not affected by the degree of tumorigenic progression in the cell lines and was not due to differences in CeReS-18 binding affinity or number of cell surface receptors per cell. However, the sensitivity of both murine fibroblasts and keratinocytes could be altered by changing the extracellular calcium concentration, such that increased extracellular calcium concentrations resulted in decreased sensitivity to CeReS-18-induced proliferation inhibition. Thus the increased sensitivity of the murine keratinocyte cell lines to CeReS-18 could be ascribed to the low calcium concentration used in their propagation. Studies are currently under way investigating the role of calcium in CeReS-18-induced growth arrest. The CeReS-18 may serve as a very useful tool to study negative growth control and the signal transduction events associated with cell cycling.

NASA Discipline Cell Biology↗

NASA NTRS2009

Cell Cycle Progression of Human Cells Cultured in Rotating Bioreactor

Space flight has been shown to alter the astronauts immune systems. Because immune performance is complex and reflects the influence of multiple organ systems within the host, scientists sought to understand the potential impact of microgravity alone on the cellular mechanisms critical to immunity. Lymphocytes and their differentiated immature form, lymphoblasts, play an important and integral role in the body's defense system. T cells, one of the three major types of lymphocytes, play a central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B cells and natural killer cells by the presence of a special receptor on their cell surface called T cell receptors. Reported studies have shown that spaceflight can affect the expression of cell surface markers. Cell surface markers play an important role in the ability of cells to interact and to pass signals between different cells of the same phenotype and cells of different phenotypes. Recent evidence suggests that cell-cycle regulators are essential for T-cell function. To trigger an effective immune response, lymphocytes must proliferate. The objective of this project is to investigate the changes in growth of human cells cultured in rotating bioreactors and to measure the growth rate and the cell cycle distribution for different human cell types. Human lymphocytes and lymphoblasts will be cultured in a bioreactor to simulate aspects of microgravity. The bioreactor is a cylindrical culture vessel that incorporates the aspects of clinostatic rotation of a solid fluid body around a horizontal axis at a constant speed, and compensates gravity by rotation and places cells within the fluid body into a sustained free-fall. Cell cycle progression and cell proliferation of the lymphocytes will be measured for a number of days. In addition, RNA from the cells will be isolated for expression of genes related in cell cycle regulations.

Parks, Kelsey↗

NASA NTRS1990

Effects of microgravity on rat bone, cartlage and connective tissues

The response to hypogravity by the skeletal system was originally thought to be the result of a reduction in weight bearing. Thus a reduced rate of new bone formation in the weight-bearing bones was accepted, when found, as an obvious result of hypogravity. However, data on non-weight-bearing tissues have begun to show that other physiological changes can be expected to occur to animals during spaceflight. This overview of the Cosmos 1887 data discusses these results as they pertain to individual bones or tissues because the response seems to depend on the architecture and metabolism of each tissue under study. Various effects were seen in different tissues from the rats flown on Cosmos 1887. The femur showed a reduced bone mineral content but only in the central region of the diaphysis. This same region in the tibia showed changes in the vascularity of bone as well as some osteocytic cell death. The humerus demonstrated reduced morphometric characteristics plus a decrease in mechanical stiffness. Bone mineral crystals did not mature normally as a result of flight, suggesting a defect in the matrix mineralization process. Note that these changes relate directly to the matrix portion of the bone or some function of bone which slowly responds to changes in the environment. However, most cellular functions of bone are rapid responders. The stimulation of osteoblast precursor cells, the osteoblast function in collagen synthesis, a change in the proliferation rate of cells in the epiphyseal growth plate, the synthesis and secretion of osteocalcin, and the movement of water into or out of tissues, are all processes which respond to environmental change. These rapidly responding events produced results from Cosmos 1887 which were frequently quite different from previous space flight data.

Doty, S.↗

NASA NTRS1998

Role of insulin-like growth factor-I in the regulation of skeletal muscle adaptation to increased loading

Adaptations in muscle mass stimulated by changes in muscle loading state entail alternations in the synthesis and degradation of myofiber proteins and the modulation of myonuclear number such that the ratio between the number of myonuclei and the size of the myofibers remains relatively constant. As depicted schematically in Figure 2.6, the literature regarding the role of IGF-in mediating muscle adaptation to alterations in loading state suggests the following conclusions: During periods of increased loading, myofibers upregulate the expression and secretion of IGF-I. Acting as an autocrine and/or paracrine growth factor, IGF-I stimulates myofiber anabolic processes. Acting as a paracrine growth factor, IGF-I also stimulates adjacent satellite cells to enter the cell cycle and proliferate. Continued myofiber production of IGF-I stimulates some satellite cells to differentiate and then fuse with myofibers, thus providing additional myonuclei in order to maintain or reestablish the myonucleus to myofiber size ratios of the enlarged myofibers.

Review, Academic↗

NASA NTRS2006

An Optimization of Pulsed ElectroMagnetic Fields Study

To date, in our research we have focused on the use of normal human neuronal progenitor (NHNP) cells because of their importance in human nervous system regeneration, development and maintenance, but we have developed 2-D and 3-D bioreactors that can accommodate any cell line. In this Project, we will include the use of tissues important for physiological regeneration: Human osteoblasts or chondrocytes, and vascular cells. Our initial results with the NHNP cells were quite startling using extremely low-level electromagnetic fields (5 microtesla at 10Hz; 6mA). The low-amplitude, rapidly time-varying electromagnetic fields exert a very potent effect on the proliferation, morphology, and gene expression of the cells in culture, both in standard 2-dimensional culture plates as well as cells organized into 3-dimensional tissue-like assemblies (TLAs) in a 3D bioreactor. We have replicated our preliminary results many, many times, have analyzed the gene expression using gene arrays (followed by Luminex analysis for protein production), and have monitored cell proliferation, orientation, morphology, and glucose metabolism, and we are confident that we have a stable and reliable model to study the control of high-level cellular processes by application of low-amplitude, time varying electromagnetic fields (TVEMF) (1, 2). In additional studies at the University of Michigan, we have been able to generate functional in vitro engineered mammalian skeletal muscle, and have employed nerve-muscle co-culture techniques to promote axonal sprouting. We believe that nearly all tissues, in particular, neural, are susceptible to the influences of low-level TVEMF.

Goodwin, Thomas J.↗

NASA NTRS1996

The leaving or Q fraction of the murine cerebral proliferative epithelium: a general model of neocortical neuronogenesis

Neurons of neocortical layers II-VI in the dorsomedial cortex of the mouse arise in the pseudostratified ventricular epithelium (PVE) through 11 cell cycles over the six embryonic days 11-17 (E11-E17). The present experiments measure the proportion of daughter cells that leave the cycle (quiescent or Q fraction or Q) during a single cell cycle and the complementary proportion that continues to proliferate (proliferative or P fraction or P; P = 1 - Q). Q and P for the PVE become 0.5 in the course of the eighth cycle, occurring on E14, and Q rises to approximately 0.8 (and P falls to approximately 0.2) in the course of the 10th cycle occurring on E16. This indicates that early in neuronogenesis, neurons are produced relatively slowly and the PVE expands rapidly but that the reverse happens in the final phase of neuronogenesis. The present analysis completes a cycle of analyses that have determined the four fundamental parameters of cell proliferation: growth fraction, lengths of cell cycle, and phases Q and P. These parameters are the basis of a coherent neuronogenetic model that characterizes patterns of growth of the PVE and mathematically relates the size of the initial proliferative population to the neuronal population of the adult neocortex.

Non-NASA Center↗

NASA NTRS1999

Nitric oxide donors, sodium nitroprusside and S-nitroso-N-acetylpencillamine, stimulate myoblast proliferation in vitro

Nitric oxide (NO) is an inter- and intracellular messenger involved in a variety of physiologic and pathophysiologic conditions. The effect of two NO donors, sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) and their effect on myoblast proliferation was examined. Both donors stimulated an increase in myoblast cell number over a range (1-10 microM) of donor concentrations. However, 50 microM SNAP inhibited myoblast proliferation. Cell numbers from cultures treated with degraded 10 microM SNAP were equivalent to the control. Therefore, it appears NO can stimulate as well as inhibit myoblast proliferation.

Non-NASA Center↗

NASA NTRS2018

Mechanoregulation of Proliferation, Differentiation, Senescence and Survival of Bone Marrow Primary Osteoprecursor Cells

Cell and animal studies conducted onboard the International Space Station and during the Shuttle program have provided extensive data illustrating bone degenerative responses to mechanical unloading in microgravity. Specifically CDKN1a/p21, an inhibitory modulator of cell cycle progression, is upregulated in osteoprecursor cells of the femur during 15-day spaceflight, suggesting that microgravity can block stem cell-based tissue regenerative process at the level of progenitor proliferation and differentiation. To study a potential role for CDKN1a/p21 in regulating osteogenic mechanosensitivity, we cultured primary bone marrow osteoprogenitor cells from CDKN1a/p21-null (p21-null) and wildtype mice with and without mechanical stimulation, and compared their morphological, proliferative, and in-vitro mineralization responses. Structural cell alterations due to mechanical stimulation were assessed by florescence labeling of f-actin cytoskeleton and focal adhesions. Mechanical stimulation of p21-null cells resulted in more pronounced cytoskeletal alignment with the axis of stretch than for wildtype cells. In addition, p21-null cells subjected to stretch loading also formed significantly more focal adhesions than wildtype cells. Combined these findings suggest that p21-null cells are structurally more responsive to stretch stimulation than the wildtype cells. Because osteoprogenitor cells are well known to respond to mechanical stimulation with increased proliferation, we also tested this response in p21-null cells. Results from those experiments show the proliferative capacity of mechanically stimulated p21-null cells far exceeded that of wildtype controls. Specifically, cell counts from 14, and 21 days post mechanical stimulation, show that p21- null cells to have a 4-fold increase in proliferation compared to wildtype. When the p21-null cell differentiation response to mechanical stimulation was evaluated, the p21-null cultuers elicited more extensive mineralization at earlier assessed timepoints than control cultures. Specifically, Von Kossa staining for mineralized matrix showed that the p21-null cells produced more than twice the mineralized surface area of wildtype cells, and at an earlier 7-day time point in culture. Taken together these results suggest that CDKN1a/p21 normally plays a role in negatively regulating osteoprogenitor proliferation and differentiation responses to mechanostimulation in bone. Findings of CDKN1a/p21's increased expression during spaceflight in microgravity also suggest not only a potential molecular mechanism for arresting regenerative bone growth in space, but potentially also a reduced impact for bone-formation-promoting exercise mechanostimulation. The findings described here constitute a novel role for p21 as a regulator of tissue regeneration in response to mechanical load stimulation, and also suggest a new promising molecular target to promote regenerative health in disuse conditions.

gravity↗

NASA NTRS1999

Regulation of expression of collagenase-3 in normal, differentiating rat osteoblasts

We investigated the regulation of collagenase-3 expression in normal, differentiating rat osteoblasts. Fetal rat calvarial cell cultures showed an increase in alkaline phosphatase activity reaching maximal levels between 7-14 days post-confluence, then declining with the onset of mineralization. Collagenase-3 mRNA was just detectable after proliferation ceased at day 7, increased up to day 21, and declined at later ages. Postconfluent cells maintained in non-mineralizing medium expressed collagenase-3 but did not show the developmental increase exhibited by cells switched to mineralization medium. Cells maintained in non-mineralizing medium continued to proliferate; cells in mineralization medium ceased proliferation. In addition, collagenase-3 mRNA was not detected in subcultured cells allowed to remineralize. These results suggest that enhanced accumulation of collagenase-3 mRNA is triggered by cessation of proliferation or acquisition of a mineralized extracellular matrix and that other factors may also be required. After initiation of basal expression, parathyroid hormone (PTH) caused a dose-dependent increase in collagenase-3 mRNA. Both the cyclic adenosine monophosphate (cAMP) analogue, 8-bromo-cAMP (8-Br-cAMP), and the protein kinase C (PKC) activator, phorbol myristate acetate, increased collagenase-3 expression, while the calcium ionophore, ionomycin, did not, suggesting that PTH was acting through the protein kinase A (PKA) and PKC pathways. Inhibition of protein synthesis with cycloheximide caused an increase in basal collagenase-3 expression but blocked the effect of PTH, suggesting that an inhibitory factor prevents basal expression while an inductive factor is involved with PTH action. In summary, collagenase-3 is expressed in mineralized osteoblasts and cessation of proliferation and initiation of mineralization are triggers for collagenase-3 expression. PTH also stimulates expression of the enzyme through both PKA and PKC pathways in the mineralizing osteoblast. Copyright 1999 Wiley-Liss, Inc.

Non-NASA Center↗

NASA NTRS2001

Stromal cells can contribute oncogenic signals

The majority of studies of neoplastic transformation have focused attention on events that occur within transformed cells. These cell autonomous events result in the disruption of molecular pathways that regulate basic activities of the cells such as proliferation, death, movement and genomic integrity. Other studies have addressed the microenvironment of tumor cells and documented its importance in supporting tumor progression. Recent work has begun to expand on these initial studies of tumor microenvironment and now provide novel insights into the possible initiation and progression of malignant cells. This review will address the transforming effect of stromal cells on epithelial components. Copyright 2001 Academic Press.

Review↗