Biomedical subjects

G David Roodman

Publications and source records attributed to G David Roodman.

44 records · Page 3Linked to original sources

PubMed2003

Role of stromal-derived cytokines and growth factors in bone metastasis.

BACKGROUND: Interactions between bone marrow-derived cytokines, growth factors, and tumors play a critical role in both the homing of tumors to the bone and the development of bone metastasis. Bone is a storehouse of latent growth factors produced by stromal cells and osteoblasts that, when activated during osteoclastic bone resorption, can enhance the growth of tumor cells. METHODS: This article reviews the role these factors may play in bone metastasis. RESULTS: Several studies have shown that breast carcinoma cells, which induce osteoclastic bone resorption, release growth factors that enhance tumor growth. In addition, bone-derived growth factors and chemokines, such as stromal cell-derived factor 1 and monocyte chemoattractant protein 1, can act as chemoattractants to attract tumor cells to bone. Finally, the interaction between tumor cells and bone marrow stromal cells can result in increased production of cytokines and growth factors, such as interleukin 6 or the ligand for the receptor activator of nuclear factor kappaB, that can enhance bone destruction, tumor growth, and angiogenesis. CONCLUSIONS: Stromal cell-derived cytokines and growth factors as well as growth factors that are released during the bone resorption process play a critical role in the development of bone metastasis. Interruption of this symbiotic relation between tumors that induce bone destruction and release of bone-derived growth factors can have beneficial effects on blocking both bone destruction and decreasing tumor burden within bone.

Bone Marrow↗

PubMed2003

AML-1A and AML-1B regulation of MIP-1alpha expression in multiple myeloma.

Macrophage inflammatory protein-1alpha (MIP-1alpha) is produced in high concentration by multiple myeloma (MM) cells in about 70% of patients, and MIP-1alpha levels correlate with their disease activity. Patients who have high levels of MIP-1alpha have a poor prognosis. Furthermore, blocking MIP-1alpha expression in an in vivo model of human MM profoundly decreases both tumor burden and bone destruction, suggesting that MIP-1alpha is an important mediator of MM bone disease. Therefore, to analyze the regulation of MIP-1alpha production in MM, we cloned the human MIP-1alpha promoter and characterized the transcription factor (TF) motifs that control MIP-1alpha expression in MM cells. The proximal region of MIP-1alpha promoter was composed of 2 sets of identical transcription regulatory regions consisting of GATA-2(+) AML-1(+) C/EBPalpha motifs. Since 2 alternatively spliced variants of the acute myeloid leukemia-1 (AML-1) class of TFs can bind the AML-1 region, AML-1A and AML-1B, the relationship between the expression levels of AML-1A or AML-1B in MM cells and their capacity to express MIP-1alpha was examined. AML-1A mRNA was relatively overexpressed compared with AML-1B in MM cell lines that produced high levels of MIP-1alpha (> 1 ng/mL per 10(6) cells per 72 hours), but AML-1A was not increased in MM cell lines that expressed less than 200 pg/mL MIP-1alpha. More importantly, the ratio of AML-1A to AML-1B mRNA levels was also increased in 3 of 3 highly purified myeloma cells from patients with MM who expressed increased amounts of MIP-1alpha. The ratio of AML-1A to AML-1B mRNA in patients with MM was 8-fold higher than in healthy controls. Transduction of AML-1B into the MM-derived MM.1S and ARH-77 cells totally blocked MIP-1alpha production, while AML-1A did not further increase the already high levels of MIP-1alpha produced by these cells. Taken together, these data demonstrate that in patients with MM who produce increased concentrations of MIP-1alpha, the relative level of AML-1B is significantly decreased compared with healthy controls. The data suggest that strategies that enhance AML-1B expression or decrease AML-1A in MM cells may be beneficial therapeutically.

Base Sequence↗

PubMed2003

Eosinophil chemotactic factor-L (ECF-L): a novel osteoclast stimulating factor.

UNLABELLED: Screening a cDNA library enriched for genes expressed in OCLs identified ECF-L. ECF-L enhanced OCL formation without increasing RANKL levels. Anti-ECF-L inhibited RANKL-induced OCL formation. These results support a potent role of ECF-L in osteoclastogenesis. INTRODUCTION: To investigate the molecular mechanisms that control osteoclastogenesis, we developed an immortalized osteoclast (OCL) precursor cell line that forms mature OCLs in the absence of stromal cells and used it to form pure populations of OCLs. MATERIALS AND METHODS: Polymerase chain reaction (PCR) selective cDNA subtraction was used to identify genes that are highly expressed in mature OCLs compared with OCL precursors employing OCL and OCL precursors derived from this cell line. RESULTS: Eosinophil chemotactic factor-L (ECF-L), a previously described chemotactic factor for eosinophils, was one of the genes identified. Conditioned media from 293 cells transfected with mECF-L cDNA, or purified ECF-L Fc protein, increased OCL formation in a dose-dependent manner in mouse bone marrow cultures treated with 10(-10) M 1,25(OH)2D3. OCLs derived from marrow cultures treated with ECF-L conditioned media formed increased pit numbers and resorption area per dentin slice compared with OCLs induced by 1,25(OH)2D3 (p < 0.01). Addition of an antisense S-oligonucleotide to mECF-L inhibited OCL formation in murine bone marrow cultures treated only with 10(-9) M 1,25(OH)2D3 compared with the sense S-oligonucleotide control. Time course studies demonstrated that ECF-L acted at the later stages of OCL formation, and chemotactic assays showed that mECF-L increased migration of OCL precursors. mECF-L mRNA was detectable in mononuclear and multinucleated cells by in situ hybridization. Interestingly, a neutralizing antibody to ECF-L blocked RANKL or 10(-9) M 1,25(OH)2D3-induced OCL formation in mouse bone marrow cultures, although ECF-L did not induce RANKL expression. CONCLUSIONS: These data show ECF-L is a previously unknown factor that is a potent mediator of OCL formation, which acts at the later stages of OCL formation and enhances the effects of RANKL.

Animals↗

PubMed2002

Multiple myeloma.

This update provides new insights into the biology, diagnosis, prognosis, and treatment of multiple myeloma (MM) and its complications. In Section I, Drs. John Shaughnessy, Jr., and Bart Barlogie first correlate global gene microarray expression profiling of patient MM samples with normal plasma cells to provide the basis for a developmental stage-based classification of MM. The powerful clinical utility of these analyses is illustrated in delineating mechanism of drug action, identifying novel therapeutic targets, and providing a molecular analysis not only of the tumor cell, but also of the tumor microenvironment, in MM. In Section II, Dr. Jean-Luc Harousseau reviews the rationale and current results of high dose therapy and autologous stem cell transplantation in MM, including optimal patient selection, prognostic factors, conditioning regimens, sources of stem cells, use of tandem transplantation, and maintenance therapy. He then provides an update on the results of allotransplantation approaches in MM, focusing on proposed methods to reduce toxicity and exploit the graft-versus-MM alloimmune effect by transplantation earlier in the disease course, T cell depletion, and nonmyeloablative transplantation. In Section III, Dr. G. David Roodman provides recent insights into the mechanisms of osteoclast activation, interactions between bone and MM cells, adhesive interactions in MM bone disease, and osteoblast suppression. These recent advances not only provide insights into pathogenesis of MM bone disease, but also form the framework for novel therapeutics. In Section IV, Dr. Kenneth Anderson provides an up-to-date discussion of the role of the bone marrow microenvironment in promoting growth, survival, drug resistance, and migration of MM cells and the signaling cascades mediating these sequelae. These studies provide the framework for evaluation of novel therapeutics targeting the MM cell-host interaction in vivo in animal models and in derived clinical trials.

Animals↗

PubMed2002

Sequence analysis of measles virus nucleocapsid transcripts in patients with Paget's disease.

It has been debated for almost 30 years whether Paget's disease of bone results from paramyxoviral infection of osteoclasts (OCs). Paramyxoviral-like nuclear inclusions are found in OCs from patients with Paget's disease, and measles virus (MV) or canine distemper virus (CDV) messenger RNA (mRNA) transcripts have been detected by in situ hybridization in bone cells from pagetic lesions. Furthermore, immunocytochemical studies have shown the presence of several paramyxoviral species in OCs from patients with Paget's disease. However, others have been unable to detect paramyxoviral transcripts in bone samples from patients with Paget's disease or marrow cultures from involved sites of patients with Paget's disease. Furthermore, no one has been able to isolate an infectious virus from pagetic bone samples or marrow cells from patients with Paget's disease, and a full-length viral gene has not been sequenced from pagetic samples. In this study, we have obtained the full-length sequence for the MV nucleocapsid (MVNP) gene in bone marrow from an involved site from a patient with Paget's disease and more than 700 base pairs (bps) of MVNP sequence in 3 other patients with Paget's disease. These sequences were undetectable in four normal marrow samples studied simultaneously. The sequences from the patients contained multiple mutations that differed from the Edmonston strain MVNP gene. These findings are consistent with the presence of a chronic MV infection in affected sites from these patients with Paget's disease.

Aged↗

PubMed2002

Role of the bone marrow microenvironment in multiple myeloma.

On June 26-27, 2001, the Sixth Research Roundtable in Multiple Myeloma, entitled "The Role of the Bone Microenvironment in Multiple Myeloma," was held and focused on the biology of cell-to-cell interactions, the mediators of bone disease, and novel treatment strategies for myeloma. Studies on cell-cell interactions showed that vascular cell adhesion molecule 1, expressed by local endothelial and stromal cells, binds to tumor cell surface integrins in which expression may be increased by tumor cell-derived chemokines such as macrophage inflammatory protein (MIP) 1alpha. These adhesive interactions increase production and release of vascular endothelial growth factor (VEGF). Studies on myeloma bone disease showed the ligand for receptor activator of nuclear transcription factor-kappaB (RANKL) was expressed on tumor cells and stromal cells associated with myeloma cells and was critical for osteoclast-induced osteolysis. Blockade of RANKL suppressed osteoclast maturation, bone resorption, and tumor development. Bisphosphonates, in addition to reducing osteoclast mobility and inducing osteoclast apoptosis, also decreased tumor cell adhesion to stroma. Immunomodulatory drugs such as thalidomide analogues targeted these tumor cell-stromal cell interactions, blocking both secretion of cytokines and activation of intracellular signaling pathways required for tumor survival and growth. These agents induced tumor cell apoptosis, decreased neovascularization, and potentiated natural killer cell activity. The proteasome inhibitor PS-341 also prevented expression of adhesion molecules and cytokines and triggered tumor cell apoptosis, even in drug-resistant cell lines, while showing minimal activity in healthy cells. In addition, potential therapeutic agents under investigation, which included RANKL antagonists, protein prenylation inhibitors, and osteoblast growth factors, were discussed.

Adjuvants, Immunologic↗

PubMed2002

SV40 T antigen and telomerase are required to obtain immortalized human adult bone cells without loss of the differentiated phenotype.

In most human primary bone cells, SV40 T-antigen expression was able to expand life span for a few passages before cells undergo growth arrest, described as crisis. In this study, telomerase activity was reconstituted in human osteoblast precursors (hPOB cells) and marrow stromal cells (Saka cells) transformed with the SV40 T antigen. Bone cells with telomerase activity were able to bypass crisis and show unlimited life span. Despite chromosomal aberrations observed in hPOB-tert cells, these immortalized precursors were able to differentiate into osteoblasts like precrisis hPOB cells. Saka-tert cells enhanced the formation of human osteoclast-like cells in a similar manner as Saka cells. These results demonstrate that reconstitution of telomerase activity in transformed SV40 T-antigen human osteoblast precursors or marrow stromal cells leads to the generation of immortalized cells with a preserved phenotype.

Antigens, Polyomavirus Transforming↗

PubMedDate not supplied

Pathogenesis of myeloma bone disease.

Myeloma bone disease is characterized by osteolytic bone destruction that is not followed by reactive new bone formation. This results in a purely lytic process, which differs from other cancers that metastasize to bone where bone destruction is followed by new bone formation. The bone destructive process in myeloma is mediated by the osteoclast (OCL), the normal bone resorbing cell. Factors that increase OCL formation and activity are produced by both myeloma cells themselves, as well as by marrow stromal cells when myeloma cells bind to marrow stromal cells. The bone destructive process releases factors that further increase the growth and survival of myeloma cells. Thus, there is a symbiotic relationship between the bone destructive process and increased growth of myeloma cells. Several studies have shown that blocking bone destruction can result in decreased tumor burden in animal models of myeloma. This overview will focus on the factors recently identified that appear to play an important role in the bone destructive process in myeloma.

Bone Diseases↗