Stimulation of cartilage growth with agonists of the non-proteolytically activated thrombin receptor

Abstract

Disclosed is a method of stimulating cartilage growth, repair or regeneration at a site in a subject in need of such growth, repair or regeneration. The method comprises the step of administering a therapeutically effective amount of an agonist of the non-proteolytically activated thrombin receptor to the site. Also disclosed is a method of stimulating the proliferation and expansion of chrondrocytes in vitro. The method comprises culturing chrondrocytes in the presence of a stimulating amount of an NPAR agonist.

Description

RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 10 / 050,688, filed Jan. 16, 2002, which is a continuation-in-part of U.S. application Ser. No. 09 / 909,348, filed Jul. 19, 2001, which claims the benefit of U.S. Provisional Application No. 60 / 219,800, filed Jul. 20, 2000. The entire teachings of the above applications are incorporated herein by reference.GOVERNMENT SUPPORT [0002] The invention was supported, in whole or in part, by grant 1 R43 AR46343-01 from the National Institutes of Health / National Institute of Arthritis and Muscoskeletal and Skin Diseases. The Government has certain rights in the invention.BACKGROUND OF THE INVENTION [0003] Unlike most tissues, cartilage does not self-repair following injury. Cartilage is an avascular tissue made up largely of cartilage specific cells, the chondrocytes, special types of collagen, and proteoglycans. The inability of cartilage to self-repair after injury, disease, or surgery is a major limit...

AI Technical Summary

Benefits of technology

[0004] It has now been found that chondrocytes isolated from articular cartilage respond to compounds which activate the non-proteolytic thrombin cell surface receptor (hereinafter “NPAR”). For example, chondrocytes express approximately 233,000 thrombin binding sites per cell with apparent affinities of approximately 0.1 nM (3000 sites) and 27 nM (230,000 sites) (Example 1). In addition, the compound TP508, an agonist of the non-proteolytic thrombin receptor, stimulates proliferation of bovine chondrocytes in culture in the presence of thrombin as a co-mitogen (Example 2A) and stimulates by itself the proliferation of rat chondrocytes cultured in three dimensional matrix culture (Example 3A). This same TP508 compound also stimulates proteoglycan synthesis as measured by the incorporation of 35S sulfate in both bovine chondrocytes (Example 2B) and 3-dimensional cultures of rat chondrocytes (Example 3B). These in vitro experiments demonstrate that NPAR agonists can stimulate proliferation and matrix production in chondrocytes isolated from articular cartilage. Additional in vivo experiments demonstrate that delivering TP508 in a sustained release formulation to rabbit trochlear grove cartilage defects which extend into the subchondral bone results in repair of the cartilage defect, including repair of subchondral bone, restoration of a normal cartilage surface and integration of the newly formed cartilage with uninjured cartilage outside of the defect area (Example 5).

Problems solved by technology

The inability of cartilage to self-repair after injury, disease, or surgery is a major limiting factor in rehabilitation of degrading joint surfaces and injury to meniscal cartilage.

In addition, the cost for cartilage repair from acute joint injury (meniscal lesions, patellar surface damage and chondromalacia) exceeds $1 billion annually.

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