transforming-growth-factor-beta and Hypercalcemia

Vascular calcification is a major risk factor for cardiovascular morbidity and mortality. A full understanding of the signalling pathways mediating vascular calcification is crucial not just because of the importance of this pathology in disease, but also for exploring potential therapeutic targets. Clinically there is a need to develop therapies to prevent or even reverse calcification in situations of atherosclerosis, chronic kidney disease, diabetes, and aging. In this brief review, we intend to explore the initial triggers, which are commonly related to calcification in different disease scenarios and examine the downstream signalling pathways that instigate the process of vascular calcification. In particular, we try to dissect these pathways and also examine cross-talk between different signalling pathways. Our focus is the vascular smooth muscle cell (VSMC) as it is ultimately the phenotypic modulation of these cells that may drive the calcification process.

Topics: Aging; Bone Morphogenetic Proteins; Calcinosis; Humans; Hypercalcemia; Hyperphosphatemia; Inflammation; Interleukin-6; Muscle, Smooth, Vascular; Oxidative Stress; Receptors, Notch; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factors; Vascular Diseases; Wnt Proteins

Extensive bone marrow necrosis and symptomatic hypercalcemia have been described independently as rare complications of chronic myeloid leukemia. Here we report a 66-year-old man who developed B cell blastic transformation 10 years after diagnosis of CML in the chronic phase. Extensive bone marrow necrosis and symptomatic hypercalcemia concurrently developed after transformation, with development of disseminated intravascular coagulation and multifocal osteolysis. Most necrotic cells were readily identifiable as blasts. Mediators related to hypercalcemia, including prostaglandin E2, transforming growth factor-alpha and transforming growth factor-beta, were significantly elevated in the serum. As far as we know, this is the first case report of chronic myeloid leukemia concurrently developing bone marrow necrosis and hypercalcemia; this association was not reported in other types of leukemia or bone marrow malignancies.

Topics: Blast Crisis; Bone Marrow; Dinoprostone; Disseminated Intravascular Coagulation; Fatal Outcome; Humans; Hypercalcemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Necrosis; Osteolysis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Parathyroid hormone-related protein (PTH-rP) was purified and cloned 10 years ago as a factor responsible for the hypercalcemia associated with malignancy. Clinical evidence supports another important role for PTH-rP in malignancy as a mediator of the bone destruction associated with osteolytic metastasis. Patients with PTH-rP positive breast carcinoma are more likely to develop bone metastasis. In addition, breast carcinoma metastatic to bone expresses PTH-rP in >90% of cases, compared with only 17% of metastasis to nonbone sites. These observations suggest that PTH-rP expression by breast carcinoma cells may provide a selective growth advantage in bone due to its ability to stimulate osteoclastic bone resorption. Furthermore, growth factors such as transforming growth factor-beta (TGF-beta), which are abundant in bone matrix, are released and activated by osteoclastic bone resorption and may enhance PTH-rP expression and tumor cell growth. To investigate the role of PTH-rP in the pathophysiology of breast carcinoma metastasis to bone, the human breast carcinoma cell line MDA-MB-231 was studied in a murine model of human breast carcinoma metastasis to bone. A series of experiments were performed in which 1) PTH-rP secretion was altered, 2) the effects of PTH-rP were neutralized, or 3) the responsiveness to TGF-beta was abolished in MDA-MB-231 cells. Cultured MDA-MB-231 cells secreted low amounts of PTH-rP that increased fivefold in response to TGF-beta. Tumor cells inoculated into the left cardiac ventricle of nude mice caused osteolytic metastasis similar to that observed in humans with breast carcinoma. When PTH-rP was overexpressed in the tumor cells, bone metastases were increased. MDA-MB-231 cells transfected with the cDNA for human preproPTH-rP secreted a tenfold greater amount of PTH-rP and caused significantly greater bone metastases when inoculated into the left cardiac ventricle of female nude mice compared with parental cells. In contrast, when the biologic effects of PTH-rP were neutralized or its production was suppressed, such metastases were decreased. Treatment of mice with a neutralizing monoclonal antibody to human PTH-rP resulted in a decrease in the development and progression of bone metastasis due to the parental MDA-MB-231 cells. Similar results were observed when mice were treated with dexamethasone, a potent glucocorticoid that suppresses production of PTH-rP by the MDA-MB-231 cells in vitro. The role of bone-derived TGF-beta in

Topics: Animals; Antineoplastic Agents, Hormonal; Bone Neoplasms; Bone Remodeling; Bone Resorption; Breast Neoplasms; Cytokines; Dexamethasone; Disease Models, Animal; Female; Humans; Hypercalcemia; Mice; Neoplasm Proteins; Osteoclasts; Parathyroid Hormone-Related Protein; Proteins; Transforming Growth Factor beta

In some patients with multiple endocrine neoplasia type 1 (MEN1) it is not possible to identify a germline mutation in the MEN1 gene. We sought to document the loss of expression and function of the MEN1 gene product, menin, in the tumors of such a patient. The proband is an elderly female patient with primary hyperparathyroidism, pancreatic islet tumor, and breast cancer. Her son has primary hyperparathyroidism. No germline MEN1 mutation was identified in the proband or her son. However, loss of heterozygosity at the MEN1 locus and complete lack of menin expression were demonstrated in the proband's tumor tissue. The proband's cultured parathyroid cells lacked the normal reduction in proliferation and parathyroid hormone secretion in response to transforming growth factor- beta. This assessment provided insight into the molecular pathogenesis of the patient and provides evidence for a critical requirement for menin in the antiproliferative action of transforming growth factor-beta.

Topics: Aged; Chromosomes, Human, Pair 11; Female; Germ-Line Mutation; Humans; Hypercalcemia; Hyperthyroidism; Liver Neoplasms; Loss of Heterozygosity; Microsatellite Repeats; Multiple Endocrine Neoplasia Type 1; Parathyroid Hormone; Parathyroid Neoplasms; Polymorphism, Genetic; Proto-Oncogene Proteins; Transforming Growth Factor beta; Tumor Cells, Cultured

Topics: Adult; Animals; Bone Neoplasms; Bone Resorption; Diphosphonates; Female; Humans; Hypercalcemia; Insulin-Like Growth Factor I; Interleukin-6; Metalloendopeptidases; Mice; Multiple Myeloma; Neoplasm Proteins; Neoplastic Cells, Circulating; Osteoblasts; Osteoclasts; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Proteins; Transforming Growth Factor beta

A 69-year-old man visited our department of neurology with symptoms of paresthesia on the lower extremities and lumbago. Biochemical examination of serum samples showed hypercalcemia (serum concentration 15.6 mg/dl). The levels of intact parathyroid hormone (i-PTH) and 1,25-dihydroxyvitamin D were suppressed, whereas parathyroid hormone-related peptide (PTHrP) was elevated up to 5.4 pM (normal range: below 0.6 pM). Additionally, bone survey revealed a punched-out lesion in radiological examinations of the skull. Bone marrow aspiration demonstrated many atypical plasma cells suggesting multiple myeloma. Nephrogenous cyclic adenosine monophosphate (cAMP), urinary deoxypyridinoline, plasma interleukin 6 (IL-6) and transforming growth factor beta (TGF beta) concentrations were elevated, whereas % of renal tubular reabsorption of phosphate (%TRP) was decreased. The immunohistochemical results demonstrated the expression of PTHrP in atypical plasma cells. These data indicated that hypercalcemia complicating multiple myeloma causes an elevation of renal calcium reabsorption and an increase of bone resorption mediated by PTHrP action.

Topics: Aged; Amino Acids; Bone Marrow; Bone Resorption; Calcium; Cyclic AMP; Humans; Hypercalcemia; Interleukin-6; Kidney; Male; Multiple Myeloma; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Proteins; Transforming Growth Factor beta; Vitamin D

Parathyroid hormone-related protein (PTHrP) is synthesized by a variety of tumors and is thought to be the main cause of the clinical syndrome of humoral hypercalcemia of malignancy (HHM). In addition to its parathyroid hormone (PTH)-like actions, novel actions of PTHrP on placental calcium transport and inhibition of in vitro osteoclast activity have been demonstrated. The fact that osteoblasts act as mediators of osteoclastic bone resorption prompted us to investigate whether nontranformed, osteoblastlike cells produce PTHrP. PTHrP has been detected in developing human fetal bones and in rat long bones in culture. For this study, osteogenic cells, CRP 5/4 and CRP 10/30, were employed. Both cell types represent clonal bone cell populations established from 1-day-old rats. While CRP 10/30 cells express the osteoblastic phenotype, CRP 5/4 cells resemble cells with preosteoblastic properties. With a radioimmunoassay (RIA), utilizing antiserum directed against the amino-terminal PTHrP(1-40), it was found that both cell types synthesize PTHrP constitutively. CRP 10/30 cells produce about twice as much as CRP 5/4 cells. Transforming growth factor-beta (TGF-beta 1) was shown to increase the synthesis of PTHrP in CRP 5/4 cells by about 2.5-fold, while in CRP 10/30 cells it caused an approximate 50% reduction of PTHrP. Employing the reverse transcriptase polymerase chain reaction (RT-PCR) technique it was found that both bone cell types express mRNA for PTHrP and that the modulation of the PTHrP mRNA levels by TGF-beta 1 in CRP 5/4, and to a lesser degree in CRP 10/30 cells, was reflected in a change in the level of PTHrP protein in the culture medium.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Autoradiography; Base Sequence; Bone Resorption; Cells, Cultured; Cloning, Molecular; Culture Media, Conditioned; Fibroblasts; Hypercalcemia; Molecular Sequence Data; Oligodeoxyribonucleotides; Osteoblasts; Osteoclasts; Parathyroid Hormone-Related Protein; Polymerase Chain Reaction; Protein Biosynthesis; Radioimmunoassay; Rats; RNA, Messenger; Transforming Growth Factor beta