An Emerging Target in the Battle against Osteoarthritis: Macrophage Polarization

Abstract

Osteoarthritis (OA) is one of the most prevalent chronic joint diseases worldwide, which causes a series of problems, such as joint pain, muscle atrophy, and joint deformities. Benefiting from some advances in the clinical treatment of OA, the quality of life of OA patients has been improved. However, the clinical need for more effective treatments for OA is still very urgent. Increasing findings show that macrophages are a critical breakthrough in OA therapy. Stimulated by different factors, macrophages are differentiated into two phenotypes: the pro-inflammatory M1 type and anti-inflammatory M2 type. In this study, various therapeutic reagents for macrophage-dependent OA treatment are summarized, including physical stimuli, chemical compounds, and biological molecules. Subsequently, the mechanisms of action of various approaches to modulating macrophages are discussed, and the signaling pathways underlying these treatments are interpreted. The NF-κB signaling pathway plays a vital role in the occurrence and development of macrophage-mediated OA, as NF-κB signaling pathway agonists promote the occurrence of OA, whereas NF-κB inhibitors ameliorate OA. Besides, several signaling pathways are also involved in the process of OA, including the JNK, Akt, MAPK, STAT6, Wnt/β-catenin, and mTOR pathways. In summary, macrophage polarization is a critical node in regulating the inflammatory response of OA. Reagents targeting the polarization of macrophages can effectively inhibit inflammation in the joints, which finally relieves OA symptoms. Our work lays the foundation for the development of macrophage-targeted therapeutic molecules and helps to elucidate the role of macrophages in OA.

Engeletin Protects Against TNF-α-Induced Apoptosis and Reactive Oxygen Species Generation in Chondrocytes and Alleviates Osteoarthritis in vivo

“…Activation of the MAPK pathway not only upregulates the expression of matrix catabolic enzymes and proinflammatory mediators but also contributes to the inhibition of other anabolic pathways, such as insulin-like growth factor 1 (IGF-1) and bone morphogenetic protein 7 (BMP7). 38 , 44 , 45 The present study proved that engeletin inhibited the NF-κB and MAPK pathways, as shown by Western blotting. This inhibitory effect may be the underlying mechanism of the therapeutic effect of engeletin.…”

Clinical-grade human dental pulp stem cells suppressed the activation of osteoarthritic macrophages and attenuated cartilaginous damage in a rabbit osteoarthritis model

“…To understand the molecular mechanism underlying the suppressive effect of hDPSCs on osteoarthritic macrophages, the MAPK pathway was chosen for investigation, as it was reported to be involved in macrophage activation in inflammatory microenvironments [26,[36][37][38][39]. OASF induced marked activation of the p38/MAPK, ERK/MAPK, and JNK/SAPK pathways in osteoarthritic macrophages.…”

“…To examine the intracellular signaling cascades, we investigated MAPK pathway protein phosphorylation in osteoarthritic macrophages because the activation of MAPK signals is critical for macrophage action [36][37][38]. The western-blotting results showed that the JNK/SAPK, ERK/MAPK, and p38/MAPK pathways in macrophages were markedly activated by OASF in a time-dependent manner (Fig.…”

Clinical-grade hDPSCs Suppressed the Activation of Osteoarthritic Macrophages and Attenuated Cartilaginous Damage in a Rabbit OA Model

“…To understand the molecular mechanism underlying the suppressive effect of hDPSCs on osteoarthritic macrophages, the MAPK pathway was chosen for investigation, as it was reported to be involved in macrophage activation in in ammatory microenvironments [29,[38][39][40]. OASF induced marked activation of the p38/MAPK, ERK/MAPK, and JNK/SAPK pathways in osteoarthritic macrophages.…”

“…To examine the intracellular signaling cascades, we investigated MAPK pathway protein phosphorylation in osteoarthritic macrophages because the activation of MAPK signals is critical for macrophage action [38][39][40]. The WB results showed that the JNK/SAPK, ERK/MAPK, and p38/MAPK pathways in macrophages were markedly activated by OASF in a time-dependent manner (Fig.…”