Granulocyte-macrophage colony-stimulating factor is a key mediator in experimental osteoarthritis pain and disease development

Abstract

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.

Proteomic Analysis Reveals Distinct Metabolic Differences Between Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Macrophage Colony Stimulating Factor (M-CSF) Grown Macrophages Derived from Murine Bone Marrow Cells*

“…These data give us profound implications in that GM-CSF affected macrophages are usually generated when our body has been influenced by microbial or aseptic inflammatory stimuli (35). Given that GM-CSF therapy has been considered to alleviate inflammatory conditions such as arthritis (36), enhanced glycolytic pathway of GM-CSF grown macrophages might be an alternative specific valuable target for macrophage mediated inflammatory diseases.…”

Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation

“…GMCSF gene-deficient (GMCSF -/-) mice, originally provided by the Ludwig Institute for Cancer Research (Parkville, Victoria, Australia), were as previously described (1,3,8). Ccl17 gene-deficient (Ccl17…”

“…GM-CSF has been shown to induce mechanical hyperalgesia (2) and to be required for the development of inflammatory and arthritic pain (1,3). We therefore examined whether pain driven by GM-CSF administration was dependent on CCL17.…”

“…As an indicator of pain, the differential distribution of weight over a 3-second period between the inflamed paw or limb relative to the noninflamed paw or limb was measured using an incapacitance meter (IITC Life Science Inc.) as before (1,3,63). This technique has previously been validated for measurement of both paw and arthritic knee pain (1, 3, 63).…”

“…In addition to its role as a proinflammatory cytokine, granulocyte macrophage colony-stimulating factor (GM-CSF) has also been implicated in bone cancer pain and in inflammatory and arthritic pain (1)(2)(3)(4). Cells of the monocyte/macrophage lineage are likely cell types involved in these functions, with other proinflammatory cytokines, such as TNF, IL-1β, IL-23, and IL-6, being implicated in possible feedback loops (5,6); GM-CSF can have a role in the biology of monocyte-derived DCs (moDCs) in autoimmune/inflammatory reactions (7,8).…”