In chronic inflammatory lesions macrophages are abundant and adapt to the low oxygen concentrations often present there. In low oxygen some cell types die by apoptosis, as reported for macrophage cell lines, while others survive better as they shift their metabolism to anaerobic glycolysis. It was found here that hypoxia prolongs the survival of murine bone marrow-derived macrophages, either in the absence or presence of low CSF-1 (M-CSF) concentrations. Although Akt activity increased in bone marrow-derived macrophages in the low oxygen conditions, the levels of both anti- and proapoptotic Bcl-2 family members decreased. Glycolysis was enhanced as judged by increased glucose uptake, glucose transporter expression, lactate dehydrogenase mRNA expression, and lactate secretion. Human monocytes responded similarly to low oxygen, and a number of genes associated with glycolysis were shown by microarray analysis and quantitative PCR to be up-regulated. Interestingly, human monocyte-derived macrophages showed evidence of enhanced glycolysis even under aerobic conditions. It is proposed that certain monocyte/macrophage populations survive better under conditions of low oxygen, thereby contributing to their increased numbers at sites of chronic inflammation and tumors; it is also proposed that as macrophages differentiate from monocytes they begin to adopt a glycolytic metabolism allowing them to adapt readily when exposed to low oxygen conditions.

IntroductionGranulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be important in the development of inflammatory models of rheumatoid arthritis and there is encouraging data that its blockade may have clinical relevance in patients with rheumatoid arthritis. The aims of the current study were to determine whether GM-CSF may also be important for disease and pain development in a model of osteoarthritis.MethodsThe role of GM-CSF was investigated using the collagenase-induced instability model of osteoarthritis. We studied both GM-CSF-/- mice and wild-type (C57BL/6) mice treated prophylactically or therapeutically with a monoclonal antibody to GM-CSF. Disease development (both early and late) was evaluated by histology and knee pain development was measured by assessment of weight distribution.ResultsIn the absence of GM-CSF, there was less synovitis and matrix metalloproteinase-mediated neoepitope expression at week 2 post disease induction, and less cartilage damage at week 6. GM-CSF was absolutely required for pain development. Therapeutic neutralization of GM-CSF not only abolished the pain within 3 days but also led to significantly reduced cartilage damage.ConclusionsGM-CSF is key to the development of experimental osteoarthritis and its associated pain. Importantly, GM-CSF neutralization by a therapeutic monoclonal antibody-based protocol rapidly and completely abolished existing arthritic pain and suppressed the degree of arthritis development. Our results suggest that it would be worth exploring the importance of GM-CSF for pain and disease in other osteoarthritis models and perhaps clinically for this form of arthritis.

ultimately lead to splenomegaly and myeloid neoplasia. In this study, we demonstrate that loss of Lyn results in a stem/ progenitor cell-intrinsic defect leading to an age-dependent increase in myeloid, erythroid, and primitive hematopoietic progenitor numbers that is independent of autoimmune disease. Despite possessing increased numbers of erythroid progenitors, and a more robust expansion of these cells following phenylhydrazine challenge, Lyn-deficient mice are more severely affected by the chemotherapeutic drug 5-fluorouracil, revealing a greater proportion of cycling progenitors. We also show that mice lacking SHIP-1 have defects in the erythroid and myeloid compartments similar to those in mice lacking Lyn or SHP-1, suggesting an intimate relationship between Lyn, SHP-1, and SHIP-1 in regulating hematopoiesis. IntroductionThe production and lineage commitment of hematopoietic cells is governed by the actions of a multitude of cytokines, hormones, and growth factors that bind to cell surface receptors activating signal transduction cascades that ultimately regulate the expression of genes that control cell fate and effector function. 1 Signal propagation in these cells is actively counterbalanced by several families of inhibitory gene products including protein tyrosine phosphatases, 2 phosphatidyl-inositol phosphatases, 3 the suppressors of cytokine signaling (SOCS) proteins, 4 and receptors bearing immunoreceptor tyrosine-based inhibitory motifs (ITIMs). 5 The central role played by tyrosine phosphorylation is exemplified by mutations in particular genes that lead to deregulation of hematopoiesis. For example, mutational activation of either the Abl 6,7 or Janus tyrosine kinases [8][9][10] leads to leukemogenesis. Loss of appropriate negative regulation of signaling may also have catastrophic consequences. For example, loss-of-function mutations within the inhibitory phosphatase Src homology 2 (SH2)-containing phosphatase-1 (SHP-1) [11][12][13] in motheaten and motheaten viable mice (Me v ), or disruption of the murine SH2-domain containing 5Ј-inositol phosphatase (SHIP-1) 14,15 gene, lead to severe perturbations in hematopoiesis with myeloid cell consolidation of the lungs of deficient mice leading to premature death. [14][15][16] Thus, the appropriate balance of positive and negative elements of signal transduction is essential for maintaining normal hematopoietic cell self-renewal, differentiation, and immune cell function.Although clearly involved in initiating tyrosine-phosphorylation cascades following hematopoietic cell stimulation, 17 Lyn has emerged as a critical enzyme responsible for establishing signaling thresholds in B cells, 18-21 myelomonocytic cells, 22,23 and mast cells. [24][25][26][27][28] Indeed, loss of Lyn kinase leads to defects in activation of inhibitory phosphatases that likely underlies the hypersensitivity of deficient cells to immunoreceptor and cytokine stimulation. 20,22,29,30 In the case of B cells and mast cells, Lyn deficiency is associated with impaired activation of ...