Pyroptosis for osteoarthritis treatment: insights into cellular and molecular interactions inflammatory

Abstract

Osteoarthritis (OA) is a widely prevalent chronic degenerative disease often associated with significant pain and disability. It is characterized by the deterioration of cartilage and the extracellular matrix (ECM), synovial inflammation, and subchondral bone remodeling. Recent studies have highlighted pyroptosis-a form of programmed cell death triggered by the inflammasome-as a key factor in sustaining chronic inflammation. Central to this process are the inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18), which play crucial roles mediating intra-articular pyroptosis through the NOD-like receptor protein 3 (NLRP3) inflammasome. This paper investigates the role of the pyroptosis pathway in perpetuating chronic inflammatory diseases and its linkage with OA. Furthermore, it explores the mechanisms of pyroptosis, mediated by nuclear factor κB (NF-κB), the purinergic receptor P2X ligand-gated ion channel 7 (P2X7R), adenosine monophosphate (AMP)-activated protein kinase (AMPK), and hypoxia-inducible factor-1α (HIF-1α). Additionally, it examines the interactions among various cellular components in the context of OA. These insights indicate that targeting the regulation of pyroptosis presents a promising therapeutic approach for the prevention and treatment of OA, offering valuable theoretical perspectives for its effective management.

Keywords: NLRP3; chondrocytes; inflammatory cytokines; osteoarthritis; pyroptosis; synoviocytes.

Figure 1

Mechanisms of classical, non-classical, and other pathways involved in pyroptosis. In the classical pathway, PRRs detect intracellular and extracellular signals, initiating the NF-κB/NLRP3 signaling cascade and activating the inflammasome. This activation leads to the cleavage of Caspase-1, which cleaved GSDMD. GSDMD then aggregates and inserts into the plasma membrane to form a membrane pore. Subsequently, Caspase-1 facilitates the release of inflammatory factors such as IL-1β and IL-18, promoting ion flow, water influx, cell swelling, and eventual cell rupture through the GSDMD pore, leading to pyroptosis. In the atypical pathway, LPS activates Pro Caspase-4/5/11, promoting the production of IL-1β and IL-18, production and inducing pyroptosis. Furthermore, Caspase-11 activation leads to intracellular K⁺ efflux and ATP release through the cleavage and modification of Pannexin-1. When ATP binds to P2X7R, it opens Ca²⁺ and Na⁺ influx channels, leading to rapid depolarization and pyroptosis. Additionally, in other pathways, TKA1 enhances Caspase-8 activation, initiating the GSDMD pore formation. Similarly, CTLs, NK cells, and the chemotherapeutic agent Caspase-3 activate the GSDME pore. These processes promote the production of inflammatory factors that ultimately contribute to pyroptosis. (Created with BioGDP.com).

Figure 2

Mechanism of pyroptosis in OA pathogenesis. The progression of OA is closely associated with NLRP3 inflammasome-mediated pyroptosis. Activation of the TLR/NF-κB signaling pathway promotes the assembly of the NLRP3 inflammasome and activates Caspase-1, which cleaves GSDMD to generate the pore-forming GSDMD-NT, releasing inflammatory cytokines such as IL-1β, IL-18, and HMGB1. The accumulation of inflammatory mediators in the joint cavity—including IL-1β, IL-18, and HMGB1—promote FLS pyroptosis, macrophage pyroptosis, chondrocyte pyroptosis and osteoclast formation. Consequently, in a persistent chronic inflammatory environment, it can cause synovial inflammation, osteophyte formation, cartilage degradation, leading to OA. (Created with BioGDP.com).

Figure 3

The signaling pathways involved in the pathophysiological development of OA, along with their corresponding targeted therapeutic drugs. During OA progression, pyroptosis in articular tissue cells is regulated through multiple molecular targets. Exposure to PAMPs or DAMPs initiates TLR-mediated activation of the NLRP3 inflammasome and Caspase-1. Subsequently, Caspase-1 and Caspase-4/5/11 cleave GSDMD to generate GSDMD-NT that oligomerize on plasma membranes, forming transmembrane pores. This process facilitates the proteolytic maturation and release of pro-inflammatory cytokines IL-1β and IL-18, ultimately triggering pyroptosis. The NLRP3 inflammasome activation is potentiated through ROS accumulation mediated by USP25/TXNIP and miR-665/MyD88 axis, which can be pharmacologically suppressed by pioglitazone and PD184352 via Nrf2/HO-1 signaling. Multiple regulatory pathways including IRF1/GBP5, NEK/OGT, miR-25-3P/CPEB1, miR-155/Smad2, and LKB1/AMPK converge on NLRP3 to modulate CC pyroptosis. Additional modulators such as miR-326/HDAC3/STAT1, Metrnl/PI3K/AKT, TGF-β/Smad2/3 signaling, along with pharmacological agents ursolic acid, loganin, and α-solanine, exert regulatory effects through NF-κB/NLRP3 pathway manipulation. Mechanical and biochemical stimuli demonstrate protective potential: ATP and moderate intensity exercise activate P2X7R ion channels, witch subsequently activate AMPK/mTOR-mediated autophagy for NLRP3 inflammasome component degradation. HMGB1 and AGN regulate FLS pyroptosis through HIF-1α/NLRP3 signaling. Macrophage pyroptosis is modulated by GYY4137 via NF-κB/NLRP3 axis, while pharmacological inhibitors Degrasyn and Ac-YVAD-cmk specifically target NLRP3 and Caspase-1 respectively to suppress this process. (Created with BioGDP.com).