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 (...

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Normal bone remodeling and pathological bone destruction have been considered to be osteoclast-driven. Osteoclasts are able to attach to bare bone surface and produce an acidic subcellular space. This leads to acid dissolution of hydroxyapatite, allowing cathepsin K to degrade the organic type I collagen-rich osteoid matrix under the acidic condition prevailing in Howship lacunae. Using a sting pH electrode, the interface membrane around a loosened total hip replacement prosthesis was found to be acidic.

hypertrophic zones, delayed formation of the secondary ossification center, and reduced skeletal growth. Isolated primary Col2a1-ICAT transgenic chondrocytes showed reduced expression of chondrocyte genes associated with maturation, and demonstrated that VEGF gene expression requires cooperative interactions between BMP2 and β-catenin signaling. Altogether the findings confirm a crucial role for Wnt/β-catenin in postnatal growth.