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AssigneeSmithKline Beecham Corporation
InventorsSusan Chubinskaya, Jeff Hutchins, Juergen Mollenhauer, Francis X. Tavares, Stephen A. Thomson, Jennings F. Worley
Estimating the term…
The present invention provides a method of treating a subject with arthritis or an arthritic disease or preventing arthritis or arthritic disease in a subject, comprising administering to the subject a therapeutically effective amount of an agent that attenuates annexin function. Also provided are various methods of screening for agents and genes that increase collagen synthesis, decrease collagen degradation, or reduce or delay apoptosis, and methods of using the identified agents or nucleic acids for attaining or maintaining cartilage homeostasis, promoting cartilage repair, increasing collagen synthesis, decreasing collagen degradation, or reducing or delaying apoptosis. The invention also provides methods of decreasing mineralization of vesicles derived from chondrocytes and of promoting endochondral bone growth using agents that attenuates annexin function. The present invention also provides a composition comprising isolated chondrocytes, an agent that attenuates annexin function, and collagen fragments or other means for challenging chondrocytes, including for example, collagen fragments, collagen peptides, or immune mediators.
A method of screening for an agent that increases collagen synthesis or decreases collagen degradation, comprising the steps of
Dependencies are inferred from the claim text.
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For testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics: involving specific cell types
Medicinal preparations containing organic active ingredients
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having seven-membered rings, e.g. azelastine, pentylenetetrazole
Having two nitrogen atoms, e.g. dilazep: 1,4-Benzodiazepines, e.g. diazepam or clozapine
Term ended 16 Oct 2021 (estimated)
USPTO file history isn’t available for this patent, so only indexed dates are shown.
1. Field of the Invention
The present invention relates to compositions and uses of modulators of annexin and of cartilage homeostasis, including therapeutic uses in the treatment and prevention of arthritis and arthritic disease.
2. Background Art
FIG. 1 shows the effect of the benzodiazepine derivative BDA452 on collagen synthesis by cultured chondrocytes challenged with fragments of collagen type II. Collagen-bound 3H-proline, an indicator of collagen synthesis, was measured in the cell layer (left) and the medium (right). Chondrocytes treated with collagen fragments alone (Col2f) had reduced levels of bound 3H-proline in the cell layer compared to chondrocytes cultured in the absence of collagen fragments (cells, no tr.). BDA452 reversed the effect of the collagen fragments in a dose-dependent fashion.
FIG. 2 shows the results of a calcium ion flux assay. Vesicles containing Calcium Green dye were incubated with annexin V in the presence or absence of collagen type II peptide and the presence or absence of BDA 452. Calcium Green is a calcium indicator (ex 480/em 510), whose fluorescence increases upon an increase in free calcium ions. Intravesicular fluorescence was subsequently measured to show the relative amount of calcium ion influx. After two hours, an increase in fluorescence signal was seen in the presence of annexin V and collagen peptide. BDA 452 reversed the annexin V/collagen effect on calcium ion flux.
FIG. 3 shows LPS induced proteoglycan release in the presence of BDA (0.5 μM and 2.0 μM). The LPS induced release in the control cultured was greatest between feeding days 9-12 in culture. Treatment of the cultures with BDA caused a dose-dependent inhibition of proteoglycan release. The highest concentration of BDA (2 μM) showed the least release of proteoglycans to the culture medium. An intermediate amount of proteoglycan release occurred in the presence of 0.5 μM BDA compared to the DMSO carrier control.
The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the Examples included therein.
Before the present methods are disclosed and described, it is to be understood that this invention is not limited to specific methods or to particular formulations, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
Throughout the specification and claims, reference is made to a number of terms that are defined to have the following meanings: