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FOXM1 activates JAK1/STAT3 pathway in human osteoarthritis cartilage cell inflammatory reaction

Runming Zeng¹, Xiaohui Lu¹, Jing Lin²

¹Department of Orthopedic Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China.

Experimental Biology and Medicine (Maywood, N.J.)

|December 10, 2020

Abstract:

Osteoarthritis (OA), the most prevalent form of arthritis disease, is characterized by destruction of articular cartilage, osteophyte development, and sclerosis of subchondral bone. Transcription factors Janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) and Forkhead box M1 (FOXM1) are key mediators of this inflammatory reaction. In this study, we investigated the interaction between JAK1/STAT3 and FOXM1 in OA. Inflammation is related to the cartilage damage, and lipopolysaccharides (LPS) are a major pro-inflammatory inducer, so LPS was utilized to stimulate chondrocytes and establish a cell-based OA model. We found LPS treatment caused a generation of inflammatory cell factors (IL-1β, IL-6, and TNF-α), and upregulation of inducible nitric oxide synthases (iNOS), cyclooxygenase-2 (COX-2), nitric oxide (NO), prostaglandin E2 (PGE2) and other inflammatory mediators. Cell viability of chondrocytes was impaired with LPS stimulation, along with an upregulation of JAK1 expression, and phosphorylation and nuclear accumulation of STAT3. The administration of STAT3 inhibitor WP1066, which abated activation and nuclear location of STAT3, depleted the effect of LPS on inflammation and cell death. Co-immunoprecipitation showed that STAT3 was able to bind to FOXM1, and deactivation of STAT3 resulted in the downregulation of FOXM1. Moreover, FOXM1 silencing inhibited the generation of inflammatory cytokines induced by LPS, and the attenuation of cell survival. These findings indicated that the interaction between JAK1/STAT3 and FOXM1 may play a key role in OA pathogenic studies, and suggest the JAK1/STAT3 pathway may be a potential target for OA therapy.

Insights

The Janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) and Forkhead box M1 (FOXM1) pathways interact to drive osteoarthritis (OA) inflammation and cartilage damage. Inhibiting JAK1/STAT3 may offer a therapeutic strategy for OA.

Area of Science:

Biochemistry
Molecular Biology
Immunology

Background:

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by cartilage destruction and inflammation.
Key transcription factors, Janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) and Forkhead box M1 (FOXM1), are implicated in OA pathogenesis.
Inflammation, induced by factors like lipopolysaccharides (LPS), significantly contributes to OA progression and chondrocyte damage.

Purpose of the Study:

To investigate the intricate interaction between the JAK1/STAT3 and FOXM1 signaling pathways in the context of osteoarthritis.
To elucidate the role of this interaction in mediating inflammatory responses and chondrocyte dysfunction during OA development.
To explore the potential of targeting the JAK1/STAT3 pathway as a therapeutic strategy for osteoarthritis.

Main Methods:

Established a cell-based osteoarthritis model using chondrocytes stimulated with lipopolysaccharides (LPS).
Assessed inflammatory mediators (IL-1β, IL-6, TNF-α, iNOS, COX-2, NO, PGE2) and chondrocyte viability.
Utilized a JAK1/STAT3 inhibitor (WP1066) and FOXM1 silencing to evaluate pathway involvement.
Employed co-immunoprecipitation to confirm the physical interaction between STAT3 and FOXM1.

Main Results:

LPS stimulation induced significant inflammation, increased inflammatory mediators, and impaired chondrocyte viability.
Upregulation of JAK1 expression and STAT3 phosphorylation/nuclear accumulation were observed post-LPS treatment.
Inhibition of STAT3 with WP1066 attenuated LPS-induced inflammation and cell death, and downregulated FOXM1 expression.
FOXM1 silencing similarly inhibited LPS-induced inflammatory cytokine production and protected chondrocyte survival, confirming its role downstream of JAK1/STAT3.

Conclusions:

The interaction between JAK1/STAT3 and FOXM1 is a critical mechanism in osteoarthritis pathogenesis.
STAT3 directly binds to FOXM1, and STAT3 activation leads to FOXM1 upregulation, driving inflammation and chondrocyte damage.
The JAK1/STAT3 signaling pathway represents a promising therapeutic target for osteoarthritis treatment.

Read full analysis

Keywords:

FOXM1 JAK1 Osteoarthritis STAT3 chondrocytes inflammation lipopolysaccharides

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