Imbalance between the mechanisms of activation and inhibition of metalloproteases in the early lesions of experimental osteoarthritis

Abstract

Levels of tissue inhibitor of metalloproteases (TIMP) and plasminogen activator (PA)/plasmin were measured and the distribution of PA was studied by immunohistochemical techniques in cartilage and synovium samples from dogs subjected to sectioning of the anterior cruciate ligament of their right knees and sham operation of their left knees (controls). Twenty-three animals were divided into 3 groups and killed at 2,4, or 8 weeks after surgery. The levels of PA and plasmin were found to be significantly elevated in the osteoarthritic (OA) knee cartilage and synovium at all times after surgery, except for levels of PA in the OA cartilage at 2 weeks. There was a positive correlation between the levels of PA and plasmin in the synovial membrane (r = 0.64, P < 0.001). In OA knees, the presence of high levels of total and active collagenase was detected in cartilage and in synovium. The levels of these 2 forms of collagenase showed a positive correlation both in cartilage (r = 0.65, P < 0.001) and in synovium (r = 0.77, P < 0.001). The levels of TIMP in cartilage from OA and sham operated knees were similar. Although the TIMP level was increased in the OA synovium, it was found 30, 1990. only in trace amounts in cartilage. Immunohistochemical studies revealed that both forms of PA, urokinasetype PA and tissue-type PA, and TIMP were present in OA tissues. In the synovium, they were found mainly in monocyte/macrophages, synovial lining cells, and blood vessel cells. In OA cartilage, PA was present only at the superficial level in chondrocytes and in cartilage matrix, whereas TIMP was present in chondrocyte lacunae throughout the full thickness of the cartilage. TIMP was also detected in the superficial level of cartilage from sham operated knees. The results of this study indicate that in OA tissues, there are conditions that favor the synthesis and activation of metalloproteases. PA and plasmin are likely to play an important role in the physiologic activation of metalloproteases, although they are probably not the only system involved in this process. The lack of increased TIMP levels in the OA cartilage, in the presence of increased metalloprotease activity, is also a possible contributing factor in the enzymatic degradation of this tissue.Osteoarthritis (OA) is a multifactorial disease in which several complex mechanisms lead to a progressive destruction of joints. The frequent involvement of diarthrodial, weight-bearing joints is largely responsible for the morbidity of OA. The primary changes seem to appear in the articular cartilage and involve both extrinsic and intrinsic factors. Among the latter, anatomic or mechanical disturbances may be of major importance in the development of OA (1). According to the mechanical factors involved in this disease, researchers have developed several experimental animal models of OA (2). One of the difficulties with many of these models is that the lesions created are often rapidly progressive and very severe.

Human Osteoarthritic Chondrocytes Possess an Increased Number of Insulin‐Like Growth Factor 1 Binding Sites but are Unresponsive to its Stimulation

“…Samples and prestained high and low molecular weight standards (Bio-Rad, Richmond, CA) were subjected Immunohistochemistry studies. Human articular cartilage was processed for immunohistochemical analysis as previously described (17). The endogenous peroxidase was quenched with 0.3% H,02 in methanol for 20 minutes at room temperature and then washed in PBS-BSA.…”

An immunohistochemical study of TIMP-3 expression in oesophageal squamous cell carcinoma

“…Excess destruction of the extracellular matrix is associated with many pathologies, including atherosclerosis, rheumatoid arthritis, and cancer progression (Liotta et al, 1980;Tryggvason et al, 1987;Palletier et al, 1990). The intricate balance between net extracellular matrix deposition and degradation is controlled by a complex system of tightly regulated protease enzymes and their endogenous inhibitors.…”

Effects of tenidap on canine experimental osteoarthritis i. morphologic and metalloprotease analysis

“…Transection of the anterior cruciate ligament of the dog knee leads to articular changes which resemble the morphologic and biochemical changes seen in human osteoarthritis (OA) (1)(2)(3). Cartilage lesions are probably related to mechanical as well as biochemical factors, including the enzymatic cleavage of matrix macromolecules (4).…”