Selective STAT3 Inhibitor Alantolactone Ameliorates Osteoarthritis via Regulating Chondrocyte Autophagy and Cartilage Homeostasis

Abstract

Osteoarthritis (OA), which is identified by chronic pain, impacts the quality of life. Cartilage degradation and inflammation are the most relevant aspects involved in its development. Signal transducer and activator of transcription 3(STAT3), a member of the STATs protein family, is associated with inflammation. Alantolactone (ALT), a sesquiterpene lactone compound, can selectively suppress the phosphorylation of STAT3. However, the pharmacological effect of ALT on OA is still imprecise. In this study, IL-1β (10 ng/ml) was applied to cartilage chondrocytes, which were treated with different concentrations of Alantolactone for 24 h. The expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2(COX2), matrix metalloproteinases (MMPs) and thrombospondin motifs-5 (ADAMTS5) were detected by western blot. Protein expression of Collagen Ⅱ was observed by western blot, safranin O staining and immunofluorescence. Manifestation of autophagy related proteins such as autophagy-related gene-5 (ATG5), P62, LC3Ⅱ/Ⅰ and PI3K/AKT/mTOR-related signaling molecules were measured by western blot and autophagic flux monitored by confocal microscopy. Expression of STAT3 and NF-κB-related signaling molecules were evaluated by western blot and immunofluorescence. In vivo, 2 mg/kg ALT or equal bulk of vehicle was engaged in the destabilization of medial meniscus (DMM) mouse models by intra-articular injection, the degree of cartilage destruction was classified by Safranin O/Fast green staining. Our findings reported that the enhance of inflammatory factors containing iNOS, COX2, MMPs and ADAMTS5 induced by IL-1β could be ameliorated by ALT. Additionally, the diminish of Collagen Ⅱ and autophagy which was stimulated by IL-1β could be alleviated by ALT. Mechanistically, STAT3, NF-κB and PI3K/AKT/mTOR signal pathways might be involved in the effect of ALT on IL-1β-induced mouse chondrocytes. In vivo, ALT protected cartilage in the DMM mouse model. Overall, this study illustrated that ALT attenuated IL-1β-induced inflammatory responses, relieved cartilage degeneration and promoted impaired autophagy via restraining of STAT3 and NF-κB signal pathways, implying its auspicious therapeutical effect for OA.

Bilobalide Exerts Anti-Inflammatory Effects on Chondrocytes Through the AMPK/SIRT1/mTOR Pathway to Attenuate ACLT-Induced Post-Traumatic Osteoarthritis in Rats

“…IL-1β induced increased OA-related protein expressions in a time and concentration dependent manner ( Tu et al, 2019 ). The stimulation of IL-1β (10 ng/ml) for 24 h could induce inflammation in chondrocytes ( Wang et al, 2019 ; Pei et al, 2021 ). IL-1β has been shown to induce the overproduction of iNOS and COX-2, which is directly relevant to the secretion of nitric oxide (NO) and prostaglandin E2 (PGE2) ( Sheu et al, 2015 ).…”

Stat3 Signaling Pathway: A Future Therapeutic Target for Bone-Related Diseases

“…Various natural compounds appear to be efficacious in bone-related diseases and hold promise as a succedaneum for synthetic compounds as the next generation of therapeutic agents. Alantolactone and lycopene inhibit IL-1 β -induced activation of NF-κB and Stat3 and attenuate chondrocyte autophagy and extracellular matrix (ECM) degradation ( Pei et al, 2021 ; Zhan et al, 2021 ). Alantolactone at 2 mg/kg alleviated medial meniscus wear and MMP13-positive cell counts in vivo ( Pei et al, 2021 ).…”

“…Alantolactone and lycopene inhibit IL-1 β -induced activation of NF-κB and Stat3 and attenuate chondrocyte autophagy and extracellular matrix (ECM) degradation ( Pei et al, 2021 ; Zhan et al, 2021 ). Alantolactone at 2 mg/kg alleviated medial meniscus wear and MMP13-positive cell counts in vivo ( Pei et al, 2021 ). By focusing on macrophages in post-trauma OA, Tian et al found that angelicin could adjust the M1/M2 ratio in synovial tissue and protect articular cartilage through the CD9/gp130/Stat3 pathway ( Tian et al, 2021 ).…”

Alantolactone: A Natural Plant Extract as a Potential Therapeutic Agent for Cancer

“…In addition, there are a few studies concerning about the correlation between ALT administration and cell autophagy in cancer cells. ALT could play a significant role in promoting impaired autophagy, facilitating to allay osteoarthritis and strengthen pancreatic cancer cells' chemosensitivity (He et al, 2018;Pei et al, 2021). Another two studies have demonstrated that treatment with ALT could significantly downregulate the cell autophagy in ALL and liver cancer cells, implying that ALT have the potential to kill cancer cells through modulating autophagy (Kang et al, 2019;Shi et al, 2020).…”