p-STAT3/DCLK1/NF-κB Axis Drives Osteoarthritis Progression by Regulating Cartilage Metabolism

Osteoarthritis (OA) is a prevalent degenerative joint disorder characterized by irreversible cartilage destruction and chronic pain, for which effective treatments with minimal side effects are limited. While signal transducer and activator of transcription 3 (STAT3) is known to be a pivotal regulator in OA pathogenesis, the specific downstream regulatory cascades of phosphorylated STAT3 (p-STAT3) in chondrocyte extracellular matrix (ECM) metabolism have remained elusive. Understanding these pathways is crucial for identifying novel therapeutic targets beyond symptomatic relief.

Researchers investigated p-STAT3 expression in human and mouse OA cartilage samples. To evaluate OA progression, they constructed chondrocyte-specific STAT3 knockout mice (Stat3fl/fl; Col2a1CreERT2) and subjected them to both spontaneous and surgically induced OA models. The study employed RNA sequencing combined with cleavage under targets and tagmentation sequencing (CUT&Tag-seq) to identify downstream targets of p-STAT3. Subsequent molecular interaction and pathway validation assays were performed to confirm the identified mechanisms.

The study revealed that p-STAT3 was significantly upregulated in OA cartilage from both human and mouse samples. Genetic knockout of STAT3 in chondrocytes significantly ameliorated OA progression in mouse models, highlighting its critical role. Mechanistically, researchers found that p-STAT3 directly bound to the doublecortin-like kinase 1 (DCLK1) promoter, leading to its transcriptional activation. This activation initiated a cascade:

DCLK1 was found to interact with IKKβ, promoting IKKβ phosphorylation and subsequent NF-κB activation. This NF-κB activation ultimately resulted in the upregulation of MMP13 (a key enzyme in cartilage degradation) and the downregulation of COL2A1 (a major component of cartilage ECM), thereby driving cartilage matrix metabolism and OA progression.