Synovial macrophages are innate immune cells that play a pivotal role in the progression of osteoarthritis (OA). When activated to a pro-inflammatory state by cartilage degradation products, macrophages produce pro-inflammatory cytokines such as IL-1 and TNF-α. These cytokines drive OA synovitis and influence the production of other pro- and anti-inflammatory cytokines, production of MMPs, and expression of aggrecanases in the OA synovium.
A drug delivery system designed to polarize synovial macrophages from a pro-inflammatory to anti-inflammatory state will inhibit production of pro-inflammatory cytokines and increase presence of anti-inflammatory cytokines within the joint. CD200 is an endogenous membrane glycoprotein that has been shown to deliver an inhibitory signal to the macrophage lineage. PLGA microspheres that encapsulate CD200 have been formulated in the Sharma Lab to target activated macrophages in vitro. By delivering CD200 in PLGA microparticles through intra-articular injection to the OA joint, we hope to (1) retain CD200 in the joint and (2) provide long-term release of CD200. In doing so, CD200 will be able to reduce inflammation long-term and reduce the number of injections needed to maintain therapeutic effect.
Macrophages are innate mediators of inflammation and wound healing. Further, macrophages can express different phenotypes, either skewed towards pro-inflammatory or anti-inflammatory characteristics, in response to different stimuli. Classically activated, pro-inflammatory, macrophages have been implicated in OA for their contributions to the inflammatory profile of the joint through cytokine and reactive oxygen species expression. We are investigating the potential of manganese dioxide (MnO2), a nanomaterial with antioxidant-like activity, to scavenge reactive oxygen species in macrophages, with the potential to mitigate macrophage inflammatory signaling.