Chemistry: analytical and immunological testing – Biospecific ligand binding assay
Patent
1985-05-02
1988-10-18
Warden, Robert J.
Chemistry: analytical and immunological testing
Biospecific ligand binding assay
435 4, 435 7, 436506, 436507, 436509, 436518, 436538, G01N 33566
Patent
active
047787686
DESCRIPTION:
BRIEF SUMMARY
The present invention is concerned with a method of clinically detecting changes occurring in articular cartilage (=the cartilage of skeletal joints). In particular, the invention is concerned with the detection of changes involving progressive destruction of the cartilage, that is, changes indicating a condition of increasing degradation of articular cartilage.
Articular cartilage comprises as its major component an extracellular matrix which assumes an important functional role and the composition of which is ccntrolled by a relatively small number of cells. This matrix is composed of (i) collagen forming a fibrous network which is of importance for the volume stability of the tissue, and (ii), as a further major component, proteoglycan having a large amount of mutually repellant electric charges due to which the tissue acquires its elasticity and its ability to resist compression. Articular cartilage, moreover, contains several other proteins, generally without known functions. An exception to this are the link proteins which participate in the formation of proteoglycan aggregates and contribute to the stability of these aggregates. Such aggregate formation appears to be a prerequisite in order for the proteoglycan and its negatively charged groups to be fixed in the tissue.
Other proteins present in articular cartilage are unknown in respect of their structure and function. Examples of these are two proteins having an apparent molecular weight of about 60 kDa. Moreover, proteins have been detected which are present in most types of cartilage and one of which has a molecular weight of about 36 kDa. Fibronectin, too, can be detected; but its occurrence is actually more conspicuous in other types of connective tissue and in blood plasma.
The structure of cartilage proteoglycans is known nowadays in its major aspects. The molecular unit is the so-called proteoglycan monomer which consists of a central protein core and a large number of carbohydrate side chains carrying a large number of negative charges and attached to the core at one of their ends. The central protein core can be conceived as being subdivided into three regions according to its carbohydrate side chains and its amino acid sequence. The side chains comprise two main types, viz., chondroitin sulfate and keratan sulfate side chains. These two types of side chains are concentrated each to one region of the protein core, to thus form a chondroitin sulfate rich region at one end of the core and a smaller keratan sulfate rich region located between said first-named region and the third core region, this latter being the hyaluronic acid-binding region which does not possess any carbohydrate side chains of the aforesaid types. The predominant proteoglycans contain about 100 chondroitin sulfate chains each with 100 negative charges, and about 50 keratan sulfate chains each with about 5 negative charges, the total of charged groups being about 10,000. Via the hyaluronic acid-binding region a great number of proteoglycan monomers are bound to hyaluronic acid which consists of a long polysaccharide chain. The aggregates thus formed have molecular weights exceeding 100.times.10.sup.6 Da. The overall compositional pattern is further complicated by the fact that articular cartilage contains two antigenically different populations of aggregating proteoglycans differing slightly inter se in respect of the nature of their side chains. By means of an immunochemical method small amounts of proteoglycans have been characterized in biopsies from cartilage (Biochem. J. (1979), p. 35-45, and Biochem. J. 187 (180), p. 687-694).
Degradation of cartilage structures is believed to involve the whole extracellular matrix,, although different parts are degraded in different stages of a cartilage disease. In an early phase, mainly proteolycans are degraded, while the collagen remains in the matrix. Unpublished results indicate that in the very beginning only the two carbohydrate rich regions are degraded and excreted to the synovial fluid, while the hyaluronic acid bindin
REFERENCES:
patent: 4153417 (1979-05-01), Hallgren et al.
patent: 4499186 (1985-02-01), Tedorescu et al.
Baker, et al., "Methods in Enzymology, vol. 83, (1983), Academic Press, pp. 216-235.
Greiling et al., X1 International Congress of Clinical Chemistry, (1982), Walter de Gruyter, pp. 635-650.
Adam, et al., Articular Synovium Int. Symp., Bruges, (1981), pp. 129-141.
Heineg.ang.rd Dick K.
Lindblad Gert
Pharmacia AB
Philpitt Fred
Warden Robert J.
Wieder Stephen C.
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