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Although osteoporosis is a disease of later life and it's major complication, fractured femur, usually occurs after the age of 75, this age group has been excluded from most trials of treatment.A group of 46 younger osteoporotic patients, median age 67yrs (range 60-74) were compared with a group of 27 older patients, median age 79 (range 75-87). The patients attended the same clinic and were treated...
Cyclical increases in hydrostatic pressure applied to cartilage or culture chondrocytes cause an increase in intracellular cAMP and proteoglycan synthesis; however the pathways by which the chondrocyte transduces the stimulus into the appropriate response are as yet largely unknown. We have previously found that cyclical pressure-induced strain of monolayer cultures of human articular chondrocytes...
We have previously shown that IGF-I and -II predominantly have mitogenic effects on human osteoblast-like cells (hOB) and stromal cells. We have also demonstrated that co-stimulation with growth hormone (hGH) enhanced this mitogenic effect, but did not improve differentiation with the exception of a significant increase in type I collagen in the stromal cells. The mechanisms behind the effects of...
Bisphosphonates have analgesic effects and they have been reported to induce a recalcification of lytic lesions in patients (pts) with tumor-induced osteolysis. We treated 34 pts with breast cancer and extensive bone metastases by 90 mg pamidronate infusions (Pam. inf.) every 3 (3-4) or every 6 (5-10) wks; 26 pts also received systemic antineoplastic therapy, but therapeutic failure was evident in...
Thyroid hormones influence growth behaviour, morphology and differentiated functions of osteoblasts (Klaushofer et al., J. Nutr. 125, 1996S-2003S, 1995). Recently effects of T3 and T4 on the cytoskeletal structure were reported (K. Banovac et al., J. Bone Miner. Res. 9, S413, 1994). In this study we therefore investigated the influence of T3 treatment on the actin cytoskeleton in MC3T3-E1 cells...
Geminal bisphosphonates contain a P-C-P bond and two side chains of variable length (R 1 and R 2 respectively). Although no clear structure-function relations of bisphosphonates have been demonstrated, R 1 is generally believed to be involved in the binding of bisphosphonates to bone mineral and not to contribute to their cellular effects. Bisphosphonates with a OH group at...
The pathogenesis of hypercalcemia of malignancy comprises increased net bone resorption as well as enhanced renal tubular reabsorption of calcium (Ca). This latter mechanism which can be detected in more than 50 % of the cases, is mainly attributed to the action of parathyroid hormone-related protein (PTHrP), which is now recognized as a major mediator of this syndrome. To evaluate the prevalence...
Many bisphosphonates (BPs) have now been studied in animals and humans. BPs are characterized by their high affinity for bone. However, it is clear that there is a wide range in relative potency of these compounds. Earlier work indicated that there is a striking difference in potency of different bisphosphonates in their ability to inhibit bone resorption in the rat Schenk model. This difference...
Osteogenic Protein-1 (OP-1, also called bone morphogenetic protein-7, BMP-7) was originally isolated from bone matrix based on its ability to induce new bone formation in vivo. The predicted amino acid sequence of the corresponding gene suggested that OP-1 was a member of the TGF-β superfamily of proteins. Preclinical studies in non-human primate models have demonstrated that OP-1 is effective in...
We have previously demonstrated rapid bone loss during the first 3 months after renal transplantation and have now assessed the ability of pamidronate to prevent this. 26 patients were randomised to receive placebo or pamidronate (0.5mg/kg intravenously) at the time of transplantation and again one month after transplantation. DXA studies were undertaken within 5 days of transplantation and 3 months...
Leukemia inhibitory factor (LIF) has pleiotropic effects on bone. To determine how LIF may modulate osteoblast activity, we have examined which signal transduction pathways are implicated in the induction of the c-fos protooncogene in the human osteoblast-like cell line, TE-85. The promoter of the c-fos gene contains several domains which are targets for intracellular signaling cascades: the Ca...
Prostaglandins (PGs) have powerful effects on bone matrix resorption and deposition. Their function includes initial suppression of bone resorption but the long-term effect is to increase the over-all activity of bone resorption. The major source of PGs in bone are the cells of osteoblast lineage. PG synthesis is highly regulated by cytokines which exert their effects on the synthesis and activity...
Extracellular ATP has been shown to increase intracellular free Ca 2+ concentration ([Ca 2+ ] i ) in a wide variety o cells, including osteoblastic cell lines, through interaction with specific receptors, P2-purinoceptors. Oscillations in [Ca 2+ ] i have been recorded in response to ATP in a number of different types of single cells. PTH is...
We have previously shown that MC3T3-E1 cells make and express FGF-2 (basic FGF) and that treatment of these cells with either FGF-2 or TGFβ stimulated production of FGF-2. In the present study, we examined the effects of 17β Estradiol (E 2 ) treatment on FGF-2 production in MC3T3-E1 cells. Cells were plated at 5,000 or 50,000/cm 2 in 6 well dishes and grown to confluence in phenol...
The biomechanical properties of bone are determined by its structure and density at all levels of hierarchical organization. In particular, the structure at the nanometer level, as investigated, e.g., by SAXS and the micrometer level, as measured by quantitative backscattered electron imaging (qBSE) are important factors in determining the quality of bone material. In this study, pieces from the...
Therapeutic efficacy of bisphosphonates depends on how much drug is present in bone. Therefore, it is important to measure the amount of bone bisphosphonate in toxicological and pharmacological studies. To measure pamidronate (3-amino-1-hydroxy-propylidene-1,1-bisphosphonate) finely ground bone was extracted with acid and the drug co-precipitated with calcium. The calcium was removed with EDTA...
Pulsed electromagnetic fields (PEMF) have been shown to be clinically beneficial in treating non-union and pseudoarthrosis after bone fracture. The osteogenic potential of rat calvarial osteoblasts is enhanced by bone morphogenetic protein-2 and 4 (BMP-2 and -4; Hughes FJ et al Endocrinology 1995; 136: 2671-2677). To investigate the implications of this with respect to PEMF treatment, we examined...
Osteoclasts require colony stimulating factor-1 (CSF-1) for differentiation, formation, fusion and survival. This cytokine binds to a cell surface receptor which is encoded by the proto-oncogenec-fms that belongs to the tyrosine kinase receptor family. In the present study, we investigated that whether CSF-1 affects morphological and functional changes of mature osteoclasts as well. Osteoclasts...
A very common metastatic site for prostate and breast cancers in humans is bone, where tumor cells attach to the extracellular matrix (ECM) and stimulate osteoclast-mediated bone resorption. Although the ability of bisphosphonates to inhibit osteoclast activity provides the rationale for their use to suppress osteolytic bone metastases in clinics, the mechanisms by which bisphosphonates inhibit tumor-induced...
Increased bone resorption after estrogen deficiency has been associated with increased cytokine production in both human and mice. Bone loss could be prevented by antibodies against the cytokines involved or their receptors in mice. Most of the reported data are obtained from peripheral blood or from ex vivo bone marrow cultures. To investigate whether cytokine transcription is affected by ovariectomy...
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