Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-12-27
2000-05-09
Criares, Theodore J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514419, 514451, 514734, 514736, A01N 4338, A01N 4316, A01N 3108
Patent
active
060605006
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Diseases associated with bone loss are usually accompanied by increased osteoclast activation. Such diseases include estrogen deficiency after the menopause, osteoporosis, primary hyperparathyroidism, malignancy, Paget's disease of bone and periodontal disease. The bone loss is caused by osteoclast activity. Osteoclasts are unique multinucleated cells within bone that are responsible for bone degradation. These are the only cells in the body known to be capable of resorbing bone. Since diseases of bone loss are associated with increased activity of these cells, it is important to understand the mechanisms by which osteoclasts are activated in these disease states, and to devise rational and therapeutic means to inhibit this activation.
The molecular mechanisms by which osteoclasts are activated are unknown. In vitro data indicate cytokines and systemic hormones with bone resorbing effects do not act directly on osteoclasts, but rather act on accessory cells in the bone marrow microenvironment and that these cells in turn are responsible for osteoclast activation (Rodan & Martin 1981, Mcsheehy & Chambers 1986). This activation may be mediated either by cell-cell contact or by locally active soluble factors. In a search for cell sources of such soluble factors, the present inventors found that a stromal cell line (C433) derived from a giant cell tumor of bone produced prodigious amounts of osteoclast-stimulating activity greater than any we found in conditioned media from cells with osteoblast characteristics (Oreffo et al., 1993).
Human giant cell tumors of bone comprise heterogeneous cell populations, including giant cells with many of the phenotypic and functional characteristics of osteoclasts as well as mononuclear cells. The multinucleated cells are positive for osteoclast surface antigens (Davies et al, 1989), for tartrate-resistant acid phosphatase (TRAP),.sup.1 possess receptors for calcitonin (Komiya et al., 1990) and lack monocyte-macrophage surface antigens (Goldring et al., 1986). The mononuclear cells comprise two distinct populations. One population does not persist in culture and is positive for Ia and monocyte-macrophage antigens (Ling et al., 1988). Another population persists in culture and resembles connective tissue stromal cells, produces Types I and III collagen, and has receptors for parathyroid hormone (Goldring et al., 1986). These latter cells can be readily established in cell culture. One cell line (C433) derived from stomal cells from a giant cell tumor is shown herein to cause greater increases in osteoclast activity as measured by accumulation of TRAP activity than any of the known osteoblast-like cell lines. This study concerns characterizing the osteoclast stimulating activity produced by this cell line. This activity is ascribed to 5-hydroxyeicosanoids, which are 5-lipoxygenase metabolites of arachidonic acid. phosphatase; HETE, hydroxyeicosatetraenoic acid; HPLC, high pressure measure liquid chromatography; LTC.sub.4, LTD.sub.4, and LTE.sub.4, leukotriene C.sub.4, leukotriene D.sub.4, and leukotriene E.sub.4, GC-MS, gas chromatography-mass spectrometry, 5-LO, 5-lipoxygenase.
Dziak and co-workers (Mohammed et al., 1989) examined the role of leukotrienes in orthodontic tooth movement, a model used to examine bone remodeling. These investigators found significant inhibition of tooth movement using the leukotriene inhibitor AA 861, even though enhanced levels of prostaglandins were detected in this treated tissue. They suggested that inhibition of LT synthesis might influence tooth movement and that prostaglandins and leukotrienes might mediate different steps in a cascade of events that results in initiation of bone remodeling.
5-lipoxygenase metabolites possess a diverse range of biological activities, especially in allergic and inflammatory responses. The molecule LTB-4 is chemotactic for polymorphonuclear leukocytes, eosinophils, lymphocytes, and monocytes and will increase adherence, oxygen radical production, and lysosomal degranulation in po
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Bonewald Lynda F.
Gallwitz Wolf E.
Mundy G.R.
Board of Regents , The University of Texas System
Criares Theodore J.
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