Purpose of review-The mitogen-activated protein (MAP) kinases are intracellular signaling proteins which play a central role in controlling the activity of pathways that regulate production and activity of multiple mediators of joint tissue destruction. The therapeutic potential of MAP kinase inhibition in osteoarthritis was reviewed. Summary-MAP kinase inhibition has the potential to slow disease progression in osteoarthritis and also might reduce pain; however, safety concerns have limited the use of general MAP kinase inhibitors in humans. Further understanding of the function of specific isoforms of the MAP kinases as well as upstream and downstream effectors may lead to the development of more specific inhibitors with less toxicity that could eventually be used as structure-modifying drugs for OA. Recent findings-Results

Objective Meniscus injury increases the risk of osteoarthritis; however, the biologic mechanism remains unknown. We hypothesized that pro-inflammatory stimulation of meniscus would increase production of matrix-degrading enzymes, cytokines and chemokines which cause joint tissue destruction and could contribute to osteoarthritis development. Design Meniscus and cartilage tissue from healthy tissue donors and total knee arthroplasties was cultured. Primary cell cultures were stimulated with pro-inflammatory factors [IL-1β, IL-6, or fibronectin fragments (FnF)] and cellular responses were analyzed by real-time PCR, protein arrays and immunoblots. To determine if NF-κB was required for MMP production, meniscus cultures were treated with inflammatory factors with and without the NF-κB inhibitor, hypoestoxide. Results Normal and osteoarthritic meniscus cells increased their MMP secretion in response to stimulation, but specific patterns emerged that were unique to each stimulus with the greatest number of MMPs expressed in response to FnF. Meniscus collagen and connective tissue growth factor gene expression was reduced. Expression of cytokines (IL-1α, IL-1β, IL-6), chemokines (IL-8, CXCL1, CXCL2, CSF1) and components of the NF-κB and tumor necrosis factor (TNF) family were significantly increased. Cytokine and chemokine protein production was also increased by stimulation. When primary cell cultures were treated with hypoestoxide in conjunction with pro-inflammatory stimulation, p65 activation was reduced as were MMP-1 and MMP-3 production. Conclusions Pro-inflammatory stimulation of meniscus cells increased matrix metalloproteinase production and catabolic gene expression. The meniscus could have an active biologic role in osteoarthritis development following joint injury through increased production of cytokines, chemokines, and matrix-degrading enzymes.

Limited understanding of the mechanisms responsible for life-threatening organ and immune failure hampers scientists' ability to design sepsis treatments. Pyruvate dehydrogenase kinase 1 (PDK1) is persistently expressed in immune-tolerant monocytes of septic mice and humans and deactivates mitochondrial pyruvate dehydrogenase complex (PDC), the gate-keeping enzyme for glucose oxidation. Here, we show that targeting PDK with its prototypic inhibitor dichloroacetate (DCA) reactivates PDC; increases mitochondrial oxidative bioenergetics in isolated hepatocytes and splenocytes; promotes vascular, immune, and organ homeostasis; accelerates bacterial clearance; and increases survival. These results indicate that the PDC/PDK axis is a druggable mitochondrial target for promoting immunometabolic and organ homeostasis during sepsis.

Objective A reduced response of articular chondrocytes to growth factors with aging could contribute to the development of osteoarthritis. The purpose of this study was to determine the effects of aging and oxidative stress on the response of human articular chondrocytes to insulin-like growth factor-1 (IGF-1) and osteogenic protein-1 (OP-1). Methods Chondrocytes isolated from normal human articular cartilage obtained from tissue donors were cultured in alginate beads or monolayer. Cells were stimulated with 50–100 ng/ml of IGF-1, OP-1, or both. Oxidative stress was induced using tert-butyl-hydroperoxide. Sulfate incorporation was used to measure proteoglycan synthesis and cell lysates to evaluate signaling proteins by immunoblotting. Confocal microscopy was used to measure nuclear translocation of Smad4. Results Chondrocytes isolated from tissue donors ranging in age from 24 to 81 years demonstrated an age-related decline in IGF-1 and IGF-1+OP-1 stimulated proteoglycan synthesis. Induction of oxidative stress inhibited both IGF-1 and OP-1 stimulated proteoglycan synthesis. Signaling studies revealed oxidative stress inhibited IGF-1 stimulated Akt phosphorylation while increasing phosphorylation of ERK and these effects were greater in cells from older donors. Oxidative stress also increased p38 phosphorylation which resulted in phosphorylation of Smad1 at the Ser206 inhibitory site and reduced Smad1 nuclear accumulation. Oxidative stress also modestly reduced OP-1 stimulated nuclear translocation of Smad4. Conclusion These results demonstrate an age-related reduction in response of human chondrocytes to IGF-1 and OP-1, two important anabolic factors in cartilage, and suggest oxidative stress may be a contributing factor by altering IGF-1 and OP-1 signaling.

Introduction Fibronectin fragments have been found in the articular cartilage and synovial fluid of patients with osteoarthritis and rheumatoid arthritis. These matrix fragments can stimulate production of multiple mediators of matrix destruction, including various cytokines and metalloproteinases. The purpose of this study was to discover novel mediators of cartilage destruction using fibronectin fragments as a stimulus.