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Data from experiments addressing the putative biological function of 24,25-dihydroxyvitamin D 3 [24,25(OH) 2 D 3 ] remain controversial. We have begun to study the role of 24,25(OH) 2 D 3 using the powerful technique of gene inactivation by homologous recombination in embryonic stem (ES) cells. A null mutation in the 25-hydroxyvitamin D 24-hydroxylase (24-OHase)...
Multinucleated giant cells (MGC) are a documented feature of diseased synovial tissue and inflammatory tissues. Evidence suggests that they are of macrophage origin and may share the same precursor cell as the osteoclast (Oc), although morphological, functional, and phenotypic differences also support the contention for separate differentation pathways. We recently identified a novel cysteine protease...
To describe structural and textural changes in bone structure, the radiographic trabecular pattern of children, aged 4-14 years, was examined using a digital image processing system. This investigation is based on data from the Nijmegen Growth Study, a mixed-longitudinal growth study comprised of three birth cohorts, which were observed for five years. Of 3075 left hand-forearm radiographs of 426...
CSF-1 is known to regulate osteoclastogenesis and bone resorption. The mechanism underlying the effect of CSF-1 on mature osteoclasts results in an increased cell spreading and arrest of resorbing activity. CSF-1 activates thec-fms tyrosine kinase cascade and affects cytoskeletal turnover. A major role in the mechanism of bone resorption is played by bone matrix proteins, which are specifically...
Little is known about the regulation of cytokine production in human marrow. We have examined secretion of cytokines by marrow obtained from patients undergoing orthopedic surgical procedures. Cells were seeded in phenol red-free αMEM, 10% fetal bovine serum, and antibiotics. Cytokines were measured by commercial ELISAs. Further, we used RT-PCR to identify marrow expression of cytochrone P450...
Osteoclast attachment to bone matrix clearly involves integrin molecules. New technology to selectively target integrin gene expression by the use of antisense oligodeoxynucleotides (ODN) has been used to study the physiological effects of different integrins in freshly isolated rabbit osteoclasts (OC). Dose response studies were performed with β1 antisense ODN on OCs adherent to glass in the presence...
Prevention of bone loss in patients (pts) with menopause induced by chemotherapy of breast cancer is a challenge, because estrogen replacement therapy is usually contra-indicated. We evaluated the effects of intermittent oral risedronate, a third generation bisphosphonate, 30 mg/day for 2 weeks every 12 weeks for 2 years (yr) in a double-blind placebo controlled study in 53 such, pts 46±4 yr old,...
The US Multicenter Study of cyclical etidronate (E) has shown it to be an effective and well-tolerated treatment for postmenopausal osteoporosis through 5 years (Licata et al., J Bone Mineral Res 1993;8[suppl 1]:S141). To assess the effects of continued treatment with E for an additional 2 years (7 years total for some patients), and the effects of discontinuing treatment for 2 years, patients who...
Studies of the structure-activity relationships of bisphosphonates (BPs) indicate that BPs with nitrogen-containing alkyl side chains are potent inhibitors of osteoclast-mediated bone resorption. These nitrogen-containing BPs are also potent inhibitors of growth of amoebae of the slime mould Dictyostelium discoideum. Since the order of potency of a wide range of BPs as inhibitors of growth of Dictyostelium...
Detailed evaluation of human osteoblast differentiation has often been hampered by the availability of suitable in vitro model systems. The majority of studies described to-date have utilized osteoblast-like cells derived from osteosarcomas which naturally possess abnormal growth characetristics We describe a novel immortalized normal human bone-marrow-derived stromal cell line, TF274, with strong...
Bone destruction is a common cause of morbidity and mortality in MM, resulting from stimulation of osteoclasts by cytokines released from myeloma cells. We previously showed that the bisphosphonate pamidronate (Aredia ), an inhibitor of bone resorption, reduces SREs (pathologic fractures, radiation therapy to bone, surgery to bone, spinal cord compression) after nine monthly cycles (Phase I) in...
Previous studies have implicated matrix metalloproteinases (Wucherpfennig et al J Bone Min Res 9, 549, 1994; Everts et al, J Cell Physiol 150, 221, 1992) and cysteine proteinases (Delaisse et al BBRC 125, 441, 1984) as mediators of collagenolysis in bone by osteoclasts. Although it is known that bone collagen destruction is elevated in post-menopausal women the principal enzyme(s) involved in mediating...
Zinc (Zn) is essential for growth in humans and has been shown to have a stimulatory effect on bone growth in tissue culture. However, in one recent study Zn has been implicated in the direct inhibition of osteoclastic (OC) bone resorption. We have previously reported that Zn increases multinucleated (MNC) TRAcP +ve cell number while inhibiting resorption over 24h in co-cultures of osteoblasts (OB)...
In this study we wanted to evaluate the short-term variations in the urinary excretion of these two markers following different antiresorptive treatments. To do so we are currently following 80 post-menopausal women (less than 10 years since menopause) with a t score at the lumbar spine of at least -1, who have not taken any treatment known to affect bone turnover in the last 6 months. These women...
DXA enables response to treatment to be measured at various sites in the skeleton. We report results of spine, hip and total body DXA in a double blind placebo controlled study of cyclical Etidronate therapy in 152 post-menopausal women. All subjects were 1-10 years post-menopausal. They received either 400mg Etidronate daily or placebo Etidronate daily for 14 days followed by 500mg oral calcium...
The heterotrimeric guanine nucleotide-binding proteins (G proteins) mediate signals of various cytokines, hormones and growth factors from the extracellular space into the cell by interacting with transmembrane receptors and intracellular effectors. Most members of the multigene G protein family are ubiquitously expressed, but some are detected only in specialized cell types.Fluoride is a stimulator...
Osteopenia and inhibited longitudinal growth in childhood are serious side effects during glucocorticoid therapy. The effects of glucocorticoids on bone have been confirmed in animal experiments. Long-term glucocorticoid administration to rats results in reduced body weights, reduced bone growth (length and cross-sectional area), and bone strength. Glucocorticoid treatment also resulted in a reduced...
To study the anabolic effects of prostaglandins (PGs) on osteoblastic differentiation, we developed a model using primary cultures of mouse bone marrow cells. 5 to 7 week old CD-1 mice were sacrificed and the bone marrow flushed out from the femur and tibia. Unfractionated marrow cells were plated at high density (1.5 - 3.5 10 6 cells/ cm 2 ) in DMEM containing 10% fetal bovine...
In multiple myeloma (MM) malignant plasma cells accumulate in the bone marrow. Little is known about the mechanisms that attract and confine the cells to this site, but specific adhesion mechanisms have been suggested to play a role. Here we studied the expression of integrins in myeloma cells of MM patients and 5 different myeloma cell lines. Cytospin preparations of the myeloma cell lines U266,...
Subcutaneous doses of 5 or 25 ug/kg alendronate 2/wk were administered to rats during 6 months since immediately after peripubertal OX (n=13,14) to describe their effects on structure and bending strength of femur diaphyses. Otherwise untreated, sham-operated or OX animals were simultaneously controlled (n=15,15).Treatment prevented OX-impairment in stiffness of bone diaphyses (load/deformation ratio,...
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