XIST/miR‐376c‐5p/OPN axis modulates the influence of proinflammatory M1 macrophages on osteoarthritis chondrocyte apoptosis

Abstract

The inflammatory microenvironment in the joints is one of the critical issues during osteoarthritis (OA) and also the main factor that may aggravate symptoms. Under inflammatory microenvironment, M1 macrophages are activated and produce large numbers of proinflammatory mediators, leading to the production of degradative enzymes, the disturbance of chondrocyte apoptosis and cartilage catabolic processes, and finally the deterioration of OA. In the present study, we reveal that the overexpression of osteopontin (OPN), a cytokine, and a matrix protein involved in arthritis and chondrocyte apoptosis in OA, could exacerbate the inflammatory microenvironment in OA via promoting the production of proinflammation cytokines and the levels of degradative enzymes in M1 macrophages, therefore, enhancing the cytotoxicity of M1 macrophage on chondrocytes. XIST expression significantly increases in OA tissue specimens. XIST serves as a competing endogenous RNA for miR-376c-5p to compete with OPN for miR-376c-5p binding, thus counteracting miR-376c-5p-mediated OPN suppression. XIST knockdown could improve the inflammatory microenvironment in OA via acting on M1 macrophages, subsequently affecting the apoptosis of cocultured chondrocytes. miR-376c-5p inhibition exerts an opposing effect on M1 macrophages and cocultured chondrocytes, as well as significantly reverses the effect of XIST knockdown. As a further confirmation, XIST and OPN mRNA expression significantly increased in OA tissues and was positively correlated in tissue samples. In summary, we provide a novel mechanism of macrophages and the inflammatory microenvironment affecting chondrocyte apoptosis. XIST and OPN might be potential targets for OA treatment, which needs further in vivo experimental confirmation. K E Y W O R D S chondrocyte, miR-376c, osteoarthritis, osteopontin, XIST

Osteopontin as a Link between Inflammation and Cancer: The Thorax in the Spotlight

“…There are conflicting reports regarding sOPN’s impact on macrophage polarization. Some of them show an M1 polarization mediated by OPN in osteoarthritis [64], whereas other research studies describe how M2 polarization is promoted by OPN fragments. This process is the result of an enhanced MMP production that degrades OPN [65].…”

LINC00623/miR-101/HRAS axis modulates IL-1β-mediated ECM degradation, apoptosis and senescence of osteoarthritis chondrocytes

“…Chondrocyte apoptosis and senescence have been detected in OA cartilage, which is associated with extracellular matrix (ECM) degradation [7,8] and participates in the initiation and development of OA [9][10][11]. Enhanced chondrocyte apoptosis has been re-ported to be significantly correlated with the severity of OA both in vitro and in vivo in studies of animals [12] and humans [13,14].…”

Mechanistic Insight on the Interaction between OPN and Integrin ανβ3 in Osteoarthritis

“…Numerous studies have investigated OPN expression in OA [ 27 ]. Li et al [ 9 ] reported that OPN affects the pathogenesis of OA by regulating the level of macrophage-degrading enzyme. Wang et al [ 28 ] showed that OPN regulates synovial cell proliferation in OA.…”

“…However, Gao et al [ 8 ] demonstrated the high expression of OPN in the knee cartilage and synovial tissue of individuals with OA. Li et al [ 9 ] suggested that OPN can increase the apoptosis of OA chondrocytes by regulating the level of degradation enzymes in M1 macrophages; these results seem to be contrary to our experimental results that OPN plays a protective role in OA. But we believe that the secretion of OPN increases with the aggravation of arthritis, because the inflammatory factors stimulate the body to cause the protective high expression of OPN, and the enhancement of the apoptosis of M1 macrophages is actually to remove the degenerated chondrocytes in the joints, which may be beneficial to the body as a whole.…”

“…OPN interacts with receptors, such as integrin and CD44, to regulate inflammation, immunity, bone metabolism, and tumor metastasis among other physiological and pathological processes [ 7 ]. Previous studies have shown that OPN is involved in the occurrence, repair, and maintenance of metabolic homeostasis of normal articular cartilage, suggesting a protective role of OPN in the pathological development of OA by regulating the components of the extracellular matrix of the articular cartilage [ 8 , 9 ]. Therefore, it is imperative to understand the difference in expression of OPN and its downstream regulatory molecules in the cartilage of individuals with OA to develop OPN as a novel therapeutic for OA.…”