Emerging Roles of Macrophage Polarization in Osteoarthritis: Mechanisms and Therapeutic Strategies

Abstract

Osteoarthritis (OA) is the most common chronic degenerative joint disease in middle‐aged and elderly people, characterized by joint pain and dysfunction. Macrophages are key players in OA pathology, and their activation state has been studied extensively. Various studies have suggested that macrophages might respond to stimuli in their microenvironment by changing their phenotypes to pro‐inflammatory or anti‐inflammatory phenotypes, which is called macrophage polarization. Macrophages accumulate and become polarized (M1 or M2) in many tissues, such as synovium, adipose tissue, bone marrow, and bone mesenchymal tissues in joints, while resident macrophages as well as other stromal cells, including fibroblasts, chondrocytes, and osteoblasts, form the joint and function as an integrated unit. In this study, we focus exclusively on synovial macrophages, adipose tissue macrophages, and osteoclasts, to investigate their roles in the development of OA. We review recent key findings related to macrophage polarization and OA, including pathogenesis, molecular pathways, and therapeutics. We summarize several signaling pathways in macrophage reprogramming related to OA, including NF‐κB, MAPK, TGF‐β, JAK/STAT, PI3K/Akt/mTOR, and NLRP3. Of note, despite the increasing availability of treatments for osteoarthritis, like intra‐articular injections, surgery, and cellular therapy, the demand for more effective clinical therapies has remained steady. Therefore, we also describe the current prospective therapeutic methods that deem macrophage polarization to be a therapeutic target, including physical stimulus, chemical compounds, and biological molecules, to enhance cartilage repair and alleviate the progression of OA.

The implications of Brain-derived neurotrophic factor in the biological activities of platelet-rich plasma.

“…In OA, the importance of macrophage polarization takes place as a tool to improve tissue healing in compartments with poor vascularization, such as diarthrodial joints [56] . In releasing growth factors such as TGF-β or IGF-1, or anti-inflammatory cytokines and peptides such as IL-10, IL-4, and TIMPs, macrophages contribute for the shifting to an anabolic state in OA joints, that ultimately leads to a 34 mitigation in tissue injury associated with catabolism and oxidative stress, especially in chondrocytes [60]. Importantly, the macrophage polarization triggered by platelet-rich plasma is one of the main therapeutic properties of PRP and further relief of OA long-term pain [58,61,62].…”

“…In this sense, the interactions between BDNF and AKT signaling could be implicated in macrophage polarization. It is known that the isoforms AKT 1 and AKT 2 directly regulate macrophage polarizationmodulating iNOS expression [75,76]. The absence of AKT 1 in macrophages promotes hyperresponsiveness to LPS and increased iNOS gene expression, exacerbating M1 inflammatory response mediated by increase in IL-1β, TNF-α, and IL-6 cytokines while the opposite is observed in the absence of AKT 2 , that leads to an exacerbation of anti-inflammatory response by upregulating Arg-1 [76].…”

“…Additionally, an enhancement on cell recruitment occurs in the knee joint, resulting on an increasing number of inflammatory cells such as macrophages, dendritic cells, neutrophils, and mast cells [75,[90][91][92][93].…”