Objective Macrophages are believed to play a critical role in the inflammation associated with the development of osteoarthritis (OA) in obesity. The objective of the study was to investigate whether short-term, systemic depletion of macrophages would mitigate OA following injury in obese mice. Methods CSF-1R–GFP+ Macrophage Fas-Induced Apoptosis (MaFIA) transgenic mice that allow conditional depletion of macrophages were placed on a high-fat diet and underwent surgery to induce knee OA. A small molecule (AP20187) was administrated to deplete macrophages in MaFIA mice. The effect of macrophage depletion on acute joint inflammation, OA severity, and arthritic bone changes were evaluated using histology and microCT. Immunohistochemistry was used to identify various immune cells. Serum and synovial fluid cytokines were also measured. Results Macrophage-depleted mice had significantly fewer M1 and M2 macrophages in the surgical operated-joints relative to controls and exhibited decreased osteophyte formation immediately following depletion. Surprisingly, macrophage depletion did not attenuate OA with obesity; instead, it induced systemic inflammation and led to a massive infiltration of CD3+ T cells and particularly neutrophils, but not B cells, into the injured joints. Macrophage-depleted mice also demonstrated markedly increased pro-inflammatory cytokines including granulocyte-colony stimulating factor (G-CSF), IL-1β, IL-6, IL-8, and TNF-α in both serum and joint synovial fluid, although animals showed trends for decreased serum insulin and leptin levels after depletion. Conclusion Our findings indicate that macrophages are vital in modulating the homeostasis of immune cells in obesity and suggest that more targeted approaches of different macrophage subtypes may be necessary to mitigate inflammation and OA with obesity.

Biomaterial scaffolds play multiple roles in cartilage tissue engineering, including controlling architecture of newly formed tissue while facilitating growth of embedded cells and simultaneously providing functional properties to withstand the mechanical environment within the native joint. In particular, hydrogels-with high water content and desirable transport properties-while highly conducive to chondrogenesis, often lack functional mechanical properties. In this regard, interpenetrating polymer network (IPN) hydrogels can provide mechanical toughness greatly exceeding that of individual components; however, many IPN materials are not biocompatible for cell encapsulation. In this study, an agarose and poly(ethylene) glycol IPN hydrogel is seeded with human mesenchymal stem cells (MSCs). Results show high viability of MSCs within the IPN hydrogel, with improved mechanical properties compared to constructs comprised of individual components. These properties are further strengthened by integrating the hydrogel with a 3D woven structure. The resulting fiber-reinforced hydrogels display functional macroscopic mechanical properties mimicking those of native articular cartilage, while providing a local microenvironment that supports cellular viability and function. These findings suggest that a fiber-reinforced IPN hydrogel can support stem cell chondrogenesis while allowing for significantly enhanced, complex mechanical properties at multiple scales as compared to individual hydrogel or fiber components.

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