Osteoclast differentiation of Pdk4 / bone marrow jak stat derived monocyte/macrophage lineage cells in the presence of M CSF and RANKL was suppressed, and osteoclastogenesis was impaired in the coculture of wild type BMMs and Pdk4 / osteoblasts, in which Rankl expression and promoter activity were reduced. Further, introduction of Pdk4 into Pdk4 / BMMs and osteoblasts enhanced osteoclastogenesis and Rankl expression and activated Rankl promoter. These findings indicate that upregulation of Pdk4 expression in osteoblasts and bone marrow cells after unloading is, at least in part, responsible for the enhancement of osteoclastogenesis and bone resorption after unloading. Arthritis is characterized by progressive cartilage erosion, inflammation of adjoining soft tissues and collapse of subchondral bone due to enhanced osteoclastic resorption.

Human joints are complex structures formed by synovial tissues, articular cartilage and subchondral bone tissue. Believing on the similarities of normal joints in humans and monkeys, we have employed a model of collagen induced arthritis in Macaca fascicularis in an attempt to evaluate the histological alterations caused by such condition in the order Dizocilpine extracellular matrix of the articular cartilage. Intermediate phalangeal proximal joints of six Macaca fascicularis suffering from collagen induced arthritis were extracted and fixed with 4% paraformaldehyde solution. Samples were also taken from disease free animals as controls. Tissues were embedded in paraffin or epoxy resin for histochemical and ultrastructural observations.

Paraffin sections Cellular differentiation were used for alkaline phosphatase, tartrate resistant acid phosphatase, cathepsin K, MMP 1, type II collagen, CTX II and fibronectin staining assessments. Control monkeys showed faint immunoreactivity against cathepsin K and MMP 1 in cells covering the articular cartilage and synovial tissues, indicating physiological levels of collagenous degradation. In arthritic animals, more intense cathepsin K and MMP 1 staining was observed in similar locations. ALP positive osteoblasts and TRAP reactive osteoclasts were abundant at the subchondral bone in arthritic samples, while control ones depicted fewer osteoclasts and weakly stained ALP positive osteoblasts, suggesting stimulated bone turnover in the arthritic group.

Interestingly, a thick cell layer covered the articular cartilage with arthritis, and cellular debris overlaid this thick cell layer, nonetheless, articular chondrocytes seemed intact. In arthritic joints, the synovial tissues displayed cellular debris in abundance. CTX II was seen in Bicalutamide Kalumid the superficial layer of the articular cartilage in arthritic samples, but it was virtually absent in the control group. Fibronectin also accumulated on the surface of the arthritic cartilage. Based on the evidence provided, it is possible that matrix degradation starts not from the adjacent subchondral bone, but from the most superficial region of the arthritic cartilage.