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Disruption of the PTHrP gene has been shown to lead to abnormalities in growth plate resulting in abnormal bone development. Interestingly, the number of osteoclasts appears to increase in the metaphyses of PTHrP-deficient mice bone (J Cell Biol 126: 1611, 1994). We previously reported that PTHrP is produced by primary and several clonal osteoblastic cells in vitro. In primary osteoblastic cells,...
Stromal cell-derived cytokines such as IL-11, which utilize the gp130 signal transducer may be pivotal in osteoclast development. To study the regulation of IL-11 production by primary murine osteoblasts, we used a new bioassay employing transfected Ba/F3 cells which expressed high affinity IL-11 receptors. Recombinant human IL-11 specifically stimulated proliferation of these cells in a dose dependent...
In vivo, application to limb bones of mechanical load sufficient to engender physiological strain levels stimulates almost immediate strain magnitude-related increases in osteocyte (OC) and osteoblast (OB) G6PD activity. This response also occurs in organ culture and is proceeded by the release of nitric oxide (NO) and prostacyclin (PGI 2 ). PGI 2 has been localized to both OCs and...
Twenty-eight young male adolescents (age from 13 years 6 months to 15 years 9 months) from a horseback-riding school were studied. They were studied at the end of summer (September of 1993) and, six months later, at the end of winter (March of 1994). At each timepoint their height and weight were measured and their pubertal status determined. Blood was collected and 25-hydroxyvitamin D [25(OH)D],...
Long-term socioeconomic impacts of Aredia on the evolution of bone metastases (BM) were evaluated retrospectively in a multicenter, controlled, randomized phase III trial in patients with advanced breast cancer and BM receiving first-line chemotherapy. Randomization was between chemotherapy alone vs. chemotherapy plus Aredia (45 mg, intravenously, during 1 hr, every 3 weeks until bone progression)...
We have raised a monoclonal antibody against cultured human osteoblast-like cells, which recognises a novel matrix antigen with a unique distribution in skeletal tissue. Immunocytochemistry on cryostat sections of normal human articular cartilage shows the antigen restricted to a zone immediately adjacent to the articular surface. In cartilage with evidence of degeneration, staining was observed...
Conditionally immortalised human osteoblast precursor cells were generated by retroviral transduction of a primary culture of human bone marrow stromal cells (HBMSC) with a vector comprising a temperature sensitive mutant of the SV40 large T antigen. Incubation of transduced cells at the oncogene's permissive temperature (33°C) results in maintained cell proliferation. Once large homogenous cell...
Estrogens are currently the first choice in the treatment of osteoporosis. Nevertheless, a lot of patients refuse them due to several reasons such as fear of cancer or others. In order to target estrogen directly to bone we tested several E 2 -BPs with different esterase-sensitive spacers for their local and systemic effects in vivo.Two E 2 -BPs expressing different serum cleavage...
Using co-cultures of mouse osteoblastic cells and hemopoietic cells, we have shown that osteoblastic stromal cells are prerequisite to osteoclast development through cell-cell interaction. In the present study, we developed a method for obtaining functionally active purified osteoclasts and examined whether the purified osteoclasts are capable of forming resorption pits on dentine slices without...
Growth factors and cytokines are implicated in the localised regulation of bone cell function, in an autocrine or paracrine manner. Leukaemia inhibitory factor (LIF) regulates cell growth and is produced by a variety of tissues, including bone. This cytokine is secreted in elevated levels in septic shock and various inflammatory conditions. Previously we have shown that recombinant human (rh)LIF...
Studies of human growth plate differentiation and function using isolated cells is not practical due to the difficulties of obtaining human growth plate tissue for analysis. Such problems would be alleviated, however, if it were possible to produce cell lines derived from human growth plate which maintain the appropriate chondrocyte phenotype. Here we report the establishment of a human foetal cell...
Introduction: Morphologic study of the three-dimensional structure of articular cartilage chondrocytes using Scanning Electron Microscopy (SEM) is of importance in research of both normal and pathologic cartilage. Rapid and reproducible good fixation over all cartilage layers is difficult to perform. This problem is addressed with the application of microwave enhanced fixation and staining optimised...
The aim of this study was to investigate the effect of a third generation bisphosphonate (CGP 42'446) on the bone and cartilage of the knee in a rabbit model of inflammatory arthritis (carrageenin arthritis model). Mature female New Zealand white rabbits were divided into two groups, control (n=7) or experimental (n=8). Both groups received 7 intra-articular injections of 0.3 ml of 1% carrageenin...
Bone matrix microdamage in bone matrix, evidenced as microcracks, occurs consequent to cyclic loading. Microdamage caused by in vivo loading has been described in human rib cortex; however, the existence and extent of microcracks in human long bone cortices are largely unknown. Using histomorphometric methods to examine the incidence and localization of microcracks in human femoral compact bone...
A secreted protein, Ecm1, specific for the clonal osteogenic stromal cell line MN7 was identified by 2D-SDS-PAGE (Mathieu et al, 1994, J. Bone Miner Res, 9, 903-913). The complete cDNA of the ECM1 gene has a length of 1.9 kb and codes for a protein of 559 amino acids. The Ecm1 mRNA is differentially spliced to a 1.5 Kb transcript. The 1.9 Kb mRNA is present in different tissues such as liver, lung...
Disphosphonates is a class of drugs which, with different potencies, different therapeutic windows, and different side effect profiles, inhibit bone resorption. Ibandronate is a third generation bisphosphonate with a promising pharmaceutical profile. The present paper describes the results from the phase II dose finding study. 180 postmenopausal women with osteoporosis defined as a bone mineral...
The cytokines IL-1 and TNFα have been shown to upregulate the transcription of matrix metalloproteinases (MMPs) as well as down regulate the synthesis of matrix components, including aggrecan and collagen type II. These cytokines are elevated in joints of patients with inflammatory arthritis and, by modulating both MMP and matrix biosynthesis, may contribute to the ultimate destruction of articular...
Pamidronate (Pam.) is the most potent of the available bisphosphonates and we evaluated the biochemical dose-response effects of a first infusion of Pam.in postmenopausal women (median 13, range 1-47 yrs after menopause) with low bone mass (T score <-1.0 at the lumbar spine or the femoral neck level). We measured in 2-hr morning fasting specimens urinary Ca (NI<0.16 mg Ca/mg Creat), hydroxyproline...
Alendronate (ALN; 4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent inhibitor of bone resorption used in the treatment of osteoporosis. Its molecular mode of action is not known. Given its bisphosphonate (BP) structure, we examined ALN effects on various phosphate transfer reactions and found that up to millimolar concentrations it did not inhibit the activities of serine/threonine phosphatase...
Healos TM , a new biodegradable calcium-phosphate mineralized matrix, is being developed for bone grafting. The mineral, a carbonated hydroxyapatite (HA), is prepared in a dispersion of collagen fibers, resulting in a uniform coating of mineral deposited onto collagen. The HA component is characterized and confirmed by X-ray powder diffraction analyses. In vitro studies show that Healos...
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