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Biomedical subjects

C Alexandre

Publications and source records attributed to C Alexandre.

At least 37 records · Page 2Linked to original sources
PubMed1991

Recruitment of new osteoblasts and osteoclasts is the earliest critical event in the pathogenesis of human multiple myeloma.

Considering the special relation of human multiple myeloma (MM) to bones, it is of importance to clarify the early steps of bone involvement in this disease. In this work, using bone histomorphometry (including histoenzymologic and kinetic studies for the first time), we have evaluated the bone remodeling (i.e., bone resorption and bone formation rates) of 16 individuals with early MM in comparison with that of 10 with benign monoclonal gammopathy (BMG) and that of 17 patients with previously untreated overt MM. A significantly increased osteoblastic recruitment was observed in the individuals with early MM when compared with those with BMG (P less than 0.01). A significant (P less than 0.01) increased bone resorption (i.e., eroded surfaces, osteoclast numbers and surfaces) was observed from the early stage of MM in comparison with the BMG status where bone resorption remained within the normal range. At the tissue level, there was no difference in terms of bone resorption between early and overt MM. On the other hand, osteoblast activity was significantly reduced in patients with overt MM (P less than 0.05 by comparison with those with early MM). A significant enhancement of osteoblastic recruitment with an increased generation of new osteoclasts is an early critical event in the pathogenesis of human MM. Of particular importance is the early stimulation of osteoblasts, since these cells produce high amounts of IL-6, a potent myeloma cell growth factor and a critical cytokine for the formation of osteoclasts in the bone marrow.

Bone Development↗
PubMed1991

Alcoholic cirrhosis and osteoporosis in men: a light and scanning electron microscopy study.

Subjects with chronic alcoholism are associated with a higher prevalence of bone fractures, compared with age-matched controls. However, the pathogenesis of alcoholic osteopathy remains poorly understood. In this study, the bone cells activities and the bone matrix were studied using different techniques such as bone morphometry, scanning electron microscopy and computer reconstruction. Male patients (N = 20), aged 59.1 +/- 10.1 years, presenting a chronic decompensated alcoholic cirrhosis, were admitted into this study. A histomorphometric analysis of a transiliac bone biopsy was done after a double tetracycline labeling of the bone. A scanning electron microscopy (SEM) study was performed on eight out of the 20 patients on an additional biopsy. The bone mass was significantly decreased in cirrhotic patients. A marked defect in the osteoblastic function was observed with reduced osteoid parameters, lower mean wall thickness, and slower bone formation rate leading to a thinning of bone trabeculae. Conversely, trabecular resorption surfaces were markedly increased. SEM examination of bone biopsies was also consistent with delayed and impaired osteoblastic activity leading to extended and scalloped resorption surfaces covered by unusually thin layers of calcified collagen fibers. The reduced osteoblastic activity associated with normal osteoclastic function appears to play a major role in the pathogenesis of alcoholic osteoporosis leading to decreased bone mass with thinner trabeculae.

Aged↗
PubMed1991

Retrovirus-mediated gene transfer of a human c-fos cDNA into mouse bone marrow stromal cells.

A cDNA encoding a complete human c-fos protein was isolated and inserted into two different murine MoMuLV-derived recombinant retroviruses allowing expression of c-fos protein in different cell types. One c-fos-expressing retrovirus, chosen for its ability to express high levels of proteins in fibroblast-like cells, was shown to potentiate long-term cultures of mouse bone marrow stromal cells in vitro and therefore constitutes a potential tool for immortalizing such cells. Moreover, when tested in an in vitro differentiation assay, stromal cells constitutively expressing c-fos favor the granulocyte differentiation of hematopoietic precursors. Interestingly, retroviruses expressing v-src and v-abl oncogenes, included as controls in our experiments, do not produce any detectable effects, whereas those expressing polyoma virus middle T antigen facilitate long-term growth in vitro of stromal cells that favor the macrophage differentiation pathway of bone marrow stem cells. Our observation supports the idea that constitutive expression of some oncogenes, including c-fos and polyoma virus middle T antigen, may influence cytokine production by bone marrow stromal cells.

Animals↗
PubMed1991

Four regulatory elements in the human c-fos promoter mediate transactivation by HTLV-1 Tax protein.

Expression of the human c-fos proto-oncogene is activated in trans by the Tax protein encoded by human T-cell leukemia virus type-1 (HTLV-1). Indeed, we show here that a HeLa clone stably transfected by Tax expresses Fos at a high level. We also show that multiple elements of the human c-fos promoter, i.e. the v-sis conditioned medium inducible element (SIE), the dyad symmetry element (DSE) necessary for growth factor induction, the octanucleotide direct repeat element (DR), and the cyclic AMP response element (CRE) centred at -60, can all mediate Tax transactivation. In the DSE, the 10bp central core that binds the serum response factor (SRF) is, by itself, sufficient to mediate Tax transactivation. Moreover, a CRE-binding protein is involved in Tax activation through the CRE-60 element. Since Fos is a transregulator of cellular genes, our results suggest that the oncoprotein plays a crucial role in T-cell transformation by HTLV-1 in conjunction with other Tax-inducible genes.

Base Sequence↗
PubMed1991

Transactivation of Krox-20 and Krox-24 promoters by the HTLV-1 Tax protein through common regulatory elements.

The HTLV-1 Tax protein has been shown to induce the expression of host cellular genes, some of which play crucial roles in cell proliferation and differentiation. We have examined the effect of Tax on the expression of two immediate-early genes, Krox-20 and Krox-24, which encode transcription factors. Several HTLV-1-infected T-cell lines and a HeLa cell line that constitutively expresses the Tax protein have a high level of expression of the Krox-20 and Krox-24 genes. In addition, Tax transactivates the promoters of both Krox-20 and Knox-24 in a co-transfection assay. Tax-responsive elements in Krox-20 and Krox-24 include the serum response elements (SREs) and the putative cAMP-responsive element (CRE). A correlation exists between the ability of these elements to mediate Tax transactivation and their affinity for their cognate factors, the serum response factor (SRF) or the CRE-binding protein (CREB) respectively. Since Tax is also able to transactivate the human c-fos promoter through the SRE and the CRE-60, our findings support the idea that the HTLV-1 Tax protein uses common mechanisms for transactivation of these three immediate-early genes. Deregulation of their expression may contribute to malignant transformation associated with HTLV-1 infection.

Base Sequence↗
PubMed1991

Bone histomorphometric comparison of rat tibial metaphysis after 7-day tail suspension vs. 7-day spaceflight.

Using histomorphometric analysis, we compared the effects of 7 d spaceflight (Biocosmos 1667) and 7 d tail-suspension in tibiae of 12-13 weeks old male Wistar rats. The skeletal alterations induced by both true and simulated weightlessness in the proximal tibial metaphysis consisted of an inhibition of longitudinal growth as indicated by the reduction of the primary spongiosa thickness. In both primary and secondary spongiosae, the loss of trabecular bone was more extensive in flight rats than in suspended rats. Impairment in cancellous and endocortical osteoid surfaces occurred in microgravity and 1-G conditions but with greater magnitude in the spongy space in flight rats. In suspended rats, the cancellous mineralization rate was decreased, suggesting an alteration of the formation activity. Bone resorption remained unchanged in flight rats whereas a twofold increase occurred in simulated conditions. These data support the hypothesis that mechanisms of bone loss in space are not entirely identical to those of tail-suspension model on Earth. New experiments allowing comparison between actual spaceflight and spaceflight simulations must be developed in order to explore common alterations and to understand differential mechanisms in the bone system.

Animals↗
PubMed1990

Micro-osteoclast resorption as a characteristic feature of B-cell malignancies other than multiple myeloma.

Multiple myeloma (MM) is characterized by the presence of lytic bone lesion and frequent hypercalcaemia. These are due to an excessive osteoclastic resorption in association with a low bone formation, as demonstrated by bone histomorphometry. Conversely, B-cell malignancies other than MM are rarely associated with lytic bone lesion and/or hypercalcaemia. In this study we have analysed quantitative bone histology in 65 patients with B-cell malignancies other than MM at diagnosis: chronic lymphocytic leukaemia (CLL, n = 20), non-Hodgkin's lymphoma (NHL, n = 25), Waldenström's disease (WD, n = 14), hairy cell leukaemia (HCL, n = 6). Fifty patients presented no clinical evidence of increased bone resorption, including no lytic bone lesions radiologically detectable and/or no hypercalcaemia. 80% of these patients (40/50) had increased bone resorption parameter using quantitative bone histology, including 19/29 (65.5%) patients with CLL or WD and 21/21 (100%) patients with NHL or HCL (P less than 0.01). As a control group, seven patients lacking bone marrow involvement on bone sample presented no excessive bone resorption. However, eight patients presented lytic bone lesions and/or hypercalcaemia. All of these patients had increased resorption parameters with high numbers of osteoclasts per surface trabecular bone (mean = 35.3), as opposed to the patients lacking lytic bone lesions and/or hypercalcaemia (mean = 6.6, n = 28) and to normal individuals (mean +/- SD = 3.8 +/- 1.7 and 6.3 +/- 2.6, respectively before and after 60 years). In all the cases, excessive histologic bone resorption was mediated by mononuclear small osteoclasts (mean osteoclast length +/- SD = 27.3 +/- 4.1 as compared to normal range = 35.0 +/- 1.0, P less than 0.001). In different in vitro models, these small mononuclear osteoclasts are considered as progenitors. These data suggest an abnormal osteoclast differentiation in B-cell malignancies other than MM, probably due to differences in the production of local factors acting on bone remodelling.

Adult↗
PubMed1990

Osteoblast stimulation in multiple myeloma lacking lytic bone lesions.

The reasons why some patients with multiple myeloma (MM) do not develop severe bone loss, or even develop sclerotic bone lesions, remain unclear. In order to answer this question at the cellular and tissue level, we evaluated the histological bone condition of 10 patients with MM who never developed lytic bone lesions during the course of their disease (including two patients with sclerotic MM). Myeloma-induced bone changes in the close vicinity of myeloma cells were evaluated by quantitative histology (bone histomorphometry). All 10 patients presented a significantly increased osteoblastic activity. This was associated with an increased bone resorption in seven of the 10 cases. Three patients had a pure osteoblastic presentation. These features were the reverse of the pattern observed in seven patients with lytic bone lesions: increased bone resorption with decreased bone formation. Almost all of these 10 patients showing excessive osteoblastic activity had increased serum bone gla protein levels, a specific marker of bone formation. Finally, 90% of these patients were lambda MM (70% of them were IgG lambda MM), an immunoglobulin subtype previously associated with the sclerotic MM variants. In conclusion, a subset of patients with MM never develop severe bone loss because of the stimulation of osteoblastic activity. These patients belong to the same family as osteosclerotic MM, presenting more frequently the IgG type and lambda subtype.

Aged↗
PubMed1990

Effect of human T-cell leukemia virus type I tax protein on activation of the human vimentin gene.

We report that the expression of the vimentin gene, a cytoskeletal growth-regulated gene, is activated in trans by the Tax (p40x) transactivator protein encoded by the human T-cell leukemia virus type I. Expression of the Tax protein activates a number of cellular genes, such as those coding for the alpha chain of the high-affinity interleukin-2 receptor and interleukin-2. These findings indicate that the Tax protein is involved in the unregulated T-cell growth associated with human T-cell leukemia virus type I infection. Higher levels of vimentin mRNA were expressed in two human T-cell leukemia virus type I-transformed T cell lines, C91/PL and C81-66/45, when compared with that in Jurkat T cells. We demonstrate that this activation is conferred by the vimentin upstream flanking sequences. Indeed, enhanced activity was detected when constructs with the vimentin promoter linked to the chloramphenicol acetyltransferase gene were transfected in HeLa cells and in two cell lines of hematopoietic origin (Jurkat T lymphoblastoid cells and U937 promonocytic cells) together with a Tax expression plasmid. By introducing a series of deletions in the vimentin promoter, we further restrict these sequences to 30 base pairs, located between 241 and 210 base pairs upstream of the mRNA cap site. A 40-base-pair oligonucleotide containing this regulatory region proved sufficient to confer Tax inducibility upon a heterologous promoter linked to chloramphenicol acetyltransferase. Importantly, this segment includes an 11-base-pair promoter segment that has homology with the binding site for the NF-kappa B transactivating factor. Our findings indicate that constitutive expression of the vimentin gene under the control of the Tax protein may be relevant in understanding the progression of the lymphoproliferative process associated with human T-cell leukemia virus type I infection.

Base Sequence↗
PubMed1990

Osteoclast cytomorphometry and scanning electron microscopy of bone eroded surfaces during leukemic disorders.

Tartrate resistant acid phosphatase (TRAP) is a reliable histochemical marker of osteoclasts when used on tissue sections of undecalcified bone. This paper presents an original morphometric analysis which can be done after histochemical identification of osteoclasts. These bone resorbing cells were demonstrated on undecalcified bone biopsies from control subjects and patients presenting a malignant disease of the lymphocyte B lineage. Computerized analysis of the osteoclastic population revealed that: (1) all TRAP positive cells along bone trabeculae belong to a osteoclastic population; (2) that B cell malignancies had an increased bone resorption. At the scanning electron microscopic level small resorption bays (about 10 microns in diameter) were observed either associated or separated from eroded surfaces presenting abnormal appearance; TRAP staining of histological sections of undecalcified bone, coupled with morphometric studies, may help in the understanding of bone disease pathobiology.

Acid Phosphatase↗