Acidic cysteine endoproteinase cathepsin K in the degeneration of the superficial articular hyaline cartilage in osteoarthritis

Abstract

Objective. To measure cartilage pH in patients with osteoarthritis (OA) and to analyze the presence of cathepsin K, the recently discovered acidic endoproteinase, in phenotypically altered chondrocytes.Methods. Intraoperative measurements of the pH of clinically normal, fibrillated, superficially fissured, and deeply fissured cartilage surfaces (grades 0-3, respectively) in OA patients undergoing primary hip replacement surgery were performed with the use of a sting electrode sterilized with microbicidic plasma. Fluorescent pH probes were used for in situ assessment of cartilage matrix pH. Cathepsin K was assessed using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry methods.Results. The pH of grade 0 cartilage surfaces was 7.1 ؎ 0.4 (mean ؎ SD), compared with 6.2 ؎ 0.9 (P < 0.05), 5.7 ؎ 1.0 (P < 0.001), and 5.5 ؎ 1.0 (P < 0.001) for grades 1-3 cartilage surfaces, respectively. Fluorescent pH probes and acid-dependent autocatalytic conversion of cathepsin K into its active, low molecular weight form in cartilage confirmed these findings. Cathepsin K messenger RNA levels increased in relation to the severity of OA, and the number of cathepsin K-containing chondrocytes increased from a mean ؎ SD of 12 ؎ 3 in grade 0 cartilage surfaces to 47 ؎ 7, 50 ؎ 6, and 100 ؎ 12 in grades 1-3 cartilage surfaces, respectively (P < 0.001 for all comparisons).Conclusion. Acid-activated, but pharmacologically inhibitable, cathepsin K is induced in phenotypically altered chondrocytes in OA. The findings suggest that cathepsin K, rather than neutral matrix metalloproteinases, degrades the superficial gliding surfaces of the articular hyaline cartilage in OA.Osteoarthritis (OA) is a common and crippling degenerative joint disease that affects the elderly population. In adult cartilage, chondrocytes occupy Ͻ5% of the total tissue volume. They reside in an avascular, anoxic environment and depend on anaerobic metabolism. Articular hyaline cartilage consists of a hydrated, proteoglycan-rich matrix in which a network of type II collagen-rich fibers is embedded (1,2). The hydrated proteoglycan matrix has a high swelling pressure, which is counteracted by the stiff collagen network (2). This gives unique biomechanical properties to the articular hyaline cartilage.While depletion of proteoglycans alone is considered to be reversible, once the collagen network is destroyed, the damage is permanent, because the articular hyaline cartilage has an almost nonexistent capacity to regenerate (3-5). Therefore, degradation of type II collagen is the crucial event in the pathogenesis of OA.OA has been considered to be strictly a wearand-tear disease, in which the destruction of the collagen fiber network is mechanically induced. However, it is now widely accepted that OA is a biochemically mediSupported by clinical EVO research grants (TYH 0056, TYH 0215, TYH 0341, and TYH 8307), an Invalid Foundation 9750/2 grant, and by the Academy of Finland/Centre for Technological Advancement (TEKES)/Ministry of Education (...

Down‐regulation of cathepsin K in synovium leads to progression of osteoarthritis in rabbits

“…Cathepsin K has been considered to be a key enzyme involved in the degradation of articular cartilage, at least in the advanced and/or end stages of OA. Up-regulation of cathepsin K was observed not only in articular cartilage but also in the synovial tissue of mice and humans with advanced OA (26,32,33). Inhibition of cathepsin K could potently suppress autoimmune inflammation of the joints as well as osteoclastic bone resorption in autoimmune arthritis (34).…”

Targeting subchondral bone for treating osteoarthritis: what is the evidence?

“…This protease has also been demonstrated to be involved in OA cartilage degradation and subchondral bone alterations [8,147]. Transgenic mouse models have provided evidence supporting its important role in arthritis.…”

Membrane-Type I Matrix Metalloproteinase-Dependent Regulation of Rheumatoid Arthritis Synoviocyte Function

“…The precise role, however, that these enzymes play in RA synoviocyte-mediated tissue destruction remains the subject of speculation. Despite the facts that RA synoviocytes are currently believed to mediate the bulk of the tissue-destructive effects associated with this disease state (1)(2)(3)(4) and that the isolated cells can be shown to express multiple proteolytic enzymes in vitro (19)(20)(21)(22)(23)(24)(25)(26)(27), only a handful of studies have attempted to examine the type I/II collagenolytic properties of isolated synovial fibroblasts or tissues (28)(29)(30). In the few cases where the collagenolytic activity of RA synoviocytes has been documented (28)(29)(30), the proteolytic systems responsible for collagen degradation have not been identified directly.…”