Pentraxin 3 regulated by miR-224-5p modulates macrophage reprogramming and exacerbates osteoarthritis associated synovitis by targeting CD32

Abstract

Emerging evidence has shown an imbalance in M1/M2 macrophage polarization to play an essential role in osteoarthritis (OA) progression. However, the underlying mechanistic basis for this polarization is unknown. RNA sequencing of OA M1-polarized macrophages found highly expressed levels of pentraxin 3 (PTX3), suggesting a role for PTX3 in OA occurrence and development. Herein, PTX3 was found to be increased in the synovium and articular cartilage of OA patients and OA mice. Intra-articular injection of PTX3 aggravated, while PTX3 neutralization reversed synovitis and cartilage degeneration. No metabolic disorder or proteoglycan loss were observed in cartilage explants when treated with PTX3 alone. However, cartilage explants exhibited an OA phenotype when treated with culture supernatants of macrophages stimulated with PTX3, suggesting that PTX3 did not have a direct effect on chondrocytes. Therefore, the OA anti-chondrogenic effects of PTX3 are primarily mediated through macrophages. Mechanistically, PTX3 was upregulated by miR-224-5p deficiency, which activated the p65/NF-κB pathway to promote M1 macrophage polarization by targeting CD32. CD32 was expressed by macrophages, that when stimulated with PTX3, secreted abundant pro-inflammation cytokines that induced severe articular cartilage damage. The paracrine interaction between macrophages and chondrocytes produced a feedback loop that enhanced synovitis and cartilage damage. The findings of this study identified a functional pathway important to OA development. Blockade of this pathway and PTX3 may prevent and treat OA.

Bibliometric and visualization analysis of macrophages associated with osteoarthritis from 1991 to 2021

“…performed an RNA sequencing of OA M1-polarized macrophages and successfully identified that pentraxin 3 (PTX3) is highly expressed in OA patients. Moreover, PTX3 was upregulated when miR-224-5p was insufficient, which activated the p65/NF-κB pathway to induce M1 macrophage polarization by targeting CD32 ( 53 ). Therefore, blockade of this pathway and PTX3 may alleviate the OA development.…”

“…In addition, the mechanism research of macrophages has also drawn many researchers' attention. For example, NO was found to induce apoptosis and proinflammatory cytokines secretion, while others reported that it could protect chondrocytes and attenuates macrophagemediated inflammation (49)(50)(51)(52)(53). Therefore, exploring the mechanisms underlying on the macrophage and OA progression.…”

Naturally derived injectable hydrogels with ROS-scavenging property to protect transplanted stem cell bioactivity for osteoarthritic cartilage repair

“…Inflammatory reaction exists in synovial tissues, that is, the severity of synovitis is associated with the symptoms of OA and the progress of disease to a large extent. A large number of macrophages with different activation states were observed in the synovium of OA patients at different stages ( Yin J. et al, 2022 ; Jia et al, 2022 ). Among them, M1 phenotype macrophages are the main subgroups of inflammatory cytokines production, cartilage degradation, and osteophyte formation in the OA state, while M2 type macrophages have a protective effect on OA by secreting some anti-inflammatory factors ( Lv et al, 2022 ; Wang et al, 2022 ).…”

A Solid–Liquid Composite Lubricating “Nano‐Snowboard” for Long‐Acting Treatment of Osteoarthritis

“…Macrophages can proliferate rapidly in pathological environments and release inflammatory factors, resulting in edema of vascular dilatation tissue and cartilage destruction. [ 47 ] LPS can activate macrophages to produce many inflammatory factors (such as tumor necrosis factor alpha (TNF‐α), interleukin 1 beta (IL‐1β), and interleukin 6 (IL‐6)). DS is a kind of NSAID that can inhibit the production of inflammatory factors primarily by inhibiting COX‐2 activity.…”