Macrophage Phenotypes in Degenerative Joint Diseases

Macrophages are plastic cells and depending on their phenotype can contribute to the inflammatory state of tissues. The main objective of this thesis is to explore the involvement of macrophages, in particular the role of their phenotypes, during processes of joint degeneration. The answers of the following questions contribute to the main objective: • How are macrophages of different phenotypes involved in inflammatory tissue degeneration and degenerative joint disease? • How can modulation of macrophage phenotypes be applied to control either inflammation or their response to biomaterials? The work described in this thesis revealed that pro-inflammatory, anti-inflammatory, and tissue repair macrophages each have their own behavior and association with OA development and progression. The studies in this thesis present methods on specifically modulating a macrophage phenotype within tissue with the ultimate goal: suppressing OA progression. These methods can be interpreted as guidelines for selecting the most suitable approach for modulation while taking into account the stage of the disease, the inflammatory state of the tissue, or the type of biomaterial in case of biomaterial based joint tissue regeneration. The knowledge can be applied to use macrophage phenotype modulation as a t

Cartilage inflammation and degeneration is enhanced by pro-inflammatory (M1) macrophages in vitro, but not inhibited directly by anti-inflammatory (M2) macrophages

Objective Macrophages play a crucial role in the progression of osteoarthritis (OA). Their phenotype may range from pro-inflammatory to anti-inflammatory. The aim of this study was to evaluate the direct effects of macrophage subtypes on cartilage by culturing macrophage conditioned medium (MCM) on human articular cartilage. Design Human OA cartilage explants were cultured with MCM of pro-inflammatory M(IFNγ+TNFα), or anti-inflammatory M(IL-4) or M(IL-10) human monocyte-derived macrophages. To assess effects of anti-inflammatory macrophages, the cartilage was cultured with a combination of MCM phenotypes as well as pre-stimulated with IFNγ+TNFα cartilage before culture with MCM. The reactions of the explants were assessed by gene expression, nitric oxide (NO) production and release of glycosaminoglycans (GAGs). Results M(IFNγ+TNFα) MCM affected OA cartilage by upregulation of IL1B (Interleukin 1β), IL6, MMP13 (Matrix Metalloproteinase-13) and ADAMTS5 (A Disintegrin And Metalloproteinase with Thrombospondin Motifs-5), while inhib

Guiding synovial inflammation by macrophage phenotype modulation: An in vitro study towards a therapy for osteoarthritis

Objective: The aims of this study were to modulate inflammation in synovial explants with the compounds: dexamethasone, rapamycin, bone morphogenetic protein 7 (BMP-7) and pravastatin, and to investigate the mod

Monocyte subsets in blood correlate with obesity related response of macrophages to biomaterials in vitro

Macrophages play a key role in the foreign body response. In this study it was investigated whether obesity affects th

Macrophage phenotypes and monocyte subsets after destabilization of the medial meniscus in mice

Macrophages play an important role in the development and progression of osteoarthritis (OA). The aim of this study was to identify macrophage phenotypes in synovium and monocyte subsets in peripheral blood in C57BL/6 mice by destabilizing the medial meniscus (DMM

Sustained release of locally delivered celecoxib provides pain relief for osteoarthritis: a proof of concept in dog patients

Objective: Drug delivery platforms that allow for gradual drug release after intra-articular administration have become of much interest as a treatment strategy for osteoarthritis (OA). The aim of this study was to investigate the safety and efficacy of an intra-articular sustained release formulation containing celecoxib (CXB), a cyclooxygenase-2 (COX-2) selective inhibitor. Methods: Amino acid-based polyesteramide microspheres (PEAMs), a biodegradable and non-toxic platform, were loaded with CXB and employed in two in vivo models of arthritis: an acute inflammatory arthritis model in rats (n = 12), and a randomized controlled study in chronic OA dog patients (n = 30). In parallel, the bioactivity of sustained release of CXB was evaluated in monolayer cultures of primary dog chondrocytes under inflammatory conditions. Results: Sustained release of CXB did not alleviate acute arthritis signs in the rat arthritis model, based on pain measurements and synovitis severity. However, in OA dog patients, sustained release of CXB improved limb function as objective parameter of pain and quality of life based on gait analysis and owner questionnaires. It also decreased pain medication dependency over a 2-month period and caused no adverse effects. Prostaglandin E2 levels, a marker for inflammation, were lower in the synovial fluid of CXB-treated dog OA patients and in CXB-treated cultured dog chondrocytes. Conclusion: These results show that local sustained release of CXB is less suitable to treat acute inflammation in arthritic joints, while safe and effective in treating pain in chronic OA in dogs